Dihydropyridazinones, pyridazinones and related compounds as fungicides

ABSTRACT

This invention relates to substituted dihydropyridazinones, pyridazinones and related compounds, of the formula ##STR1## wherein A, Q, D and R1 are as defined within, compositions containing these compounds and methods of controlling agricultural and mammalian fungal diseases.

This is a divisional of application Ser. No. 08/467,384, filed Jun. 6,1995, U.S. Pat. No. 5,631,254 which is a divisional of U.S. Ser. No.08/221,229, filed Mar. 31, 1994, U.S. Pat. No. 5,552,409 which is acontinuation of U.S. Ser. No. 07/749,576, filed Aug. 28, 1991 nowabandoned; which is a CIP of U.S. Ser. No. 07/586,633, filed Sep. 21,1990 now abandoned.

This invention relates to substituted dihydropyridazinones,pyridazinones and related compounds, compositions containing thesecompounds and a method of controlling fungi by the use of a fungitoxicamount of these compounds.

Although many different types of compounds are known for use asfungicides, and, in particular, for use as agricultural fungicides,there is a continuous demand for new agricultural fungicides. Inparticular, there is a continuous demand for agricultural fungicideswhich are active against fungal diseases of rice. Accordingly, thisinvention relates to the use of a class of pyridazinones anddihydropyridazinones and related compounds in the control ofagricultural fungal diseases, particularly in rice.

Further, although different types of compounds are known for use ashuman fungicides, there remains a need for additional non-toxic,pathogenically selective compounds useful to control fungal diseases inhumans. Accordingly, this invention also relates to the use of thecompounds of the invention to control fungal diseases in humans.

The compounds used in the present invention are pyridazinone-relatedcompounds of the formula ##STR2## wherein A is --(CHR²)_(n) --CHR⁷--Z--;

--CF₂ --CF₂ --Z--;

--(CHR²)_(n) --O--Z;

--(CHR²)_(n) --S--Z--;

--O--CHR⁷ --Z--;

--CR² ═CR⁷ --Z--;

--CR² ═N--Z--;

CHR² --CR⁷ ═Y--; or

--CR² ═CR² --Y═;

D is CR⁸ or nitrogen;

Q is an aromatic group selected from ##STR3## Z is carbonyl (C═O), orthiocarbonyl (C═S); Y is carbon substituted by halo, alkoxy, alkynylthioor triazolyl;

wherein

R¹ is alkyl, hydroxyalkyl, cyanoalkyl, hydrazidal and derivativesthereof, cycloalkylalkyl, heterocyclylalkyl, phenyl, phenylalkyl,phenylcarbonyl, alkenyl, haloalkenyl, phenylalkenyl, alkynylalkenyl,alkynyl, haloalkynyl, phenylalkynyl, heterocyclyl, dialkynylheterocyclylalkynyl, cydoalkylalkynyl, alkenylalkynyl, hydroxyalkynyl,alkoxyalkynyl, alkanoyloxyalkynyl, formylalkynyl, trialkylsilylalkynyl,trialkyltinalkynyl, haloalkenylalkynyl, carboxyalkynyl, oralkoxycarbonylalkynyl;

R² and R⁸ are independently hydrogen, (C₁ -C₃)alkyl, phenyl, cyano orhalogen;

R⁷ can be hydrogen, (C₁ -C₃)alkyl, phenyl, cyano or halogen, alkynyl,alkynylalkenyl, dialkynyl, haloalkynyl, and alkenylalkynyl;

R³ and R⁶ are independently hydrogen, alkoxy or halogen;

R⁴ is hydrogen, halogen, alkoxy or nitro;

R⁵ is hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl,haloalkoxy, haloalkylthio, phenyl, phenoxy or cyano; or

R² and R³ together form a (C₁ -C₃)alkyl, (C₂ -C₃)alkylene or carbonyllink; or

R² and R⁷ together form a fused phenyl or (C₁ -C₃)cycloalkyl ring;

X is oxygen (O) or sulfur (S);

n is 0, 1 or 2; and

agronomically acceptable salts thereof.

Halo is bromo, fluoro, chloro, and iodo.

Alkyl is, for example, (C₁ -C₆)straight or branched alkyl, such asmethyl, ethyl, n-butyl or t-butyl. Hydroxyalkyl is, for example,hydroxy(C₁ -C₆)alkyl such as 1-hydroxypropyl or 3-hydroxybutyl.Cyanoalkyl is, for example, cyano(C₁ -C₆)alkyl such as cyanomethyl. Thehydrazidal moiety is, for example, terminal alkylhydride, such asacetylhydrazide, such that, for example, an embodied compound having theR¹ substituent can be 6-halophenyl-2-acetylhydrazide4,5-dihydropyridazinone. A non-terminal alkyl hydride can have organicgroups attached such as, for example, 6-halophenyl-2-N-acetyhydrazide-(N'-2,4-pentanedione-hydrazone)!-4,5-pyridazinone or,for example, 6-halophenyl-2-N-acetylhydrazide-(N'-halophenylhydrazone)!-4,5-dihydropyridazinone.Further embodiments can include cyclicyzed forms such as6-halophenyl-2-(alkyl-1-pyrazoylmethylene)-4,5-dihydropyridazinone;6-halophenyl-2-(1,3,4-oxadiazin-2-one-5-yl-methylene)-4,5-dihydropyridazinone;or 6-halophenyl-2-2,3,4-oxadiazin-2-one-3-(2'-alkynyl)-5-yl-methylene!-4,5-dihydropyridazinone.Alkynyl substituents to such cyclic compounds can include 2-pentynyl,2-butynyl and 3-halo-2-propynyl. One example can be6-(4-chlorophenyl)-2-(1,3,4-oxadiazin-2-one-3-(3'-iodopropargyl)-5-yl-methylene!-4,5-dihydropyridazinone.

An example of a heterocycyl alkyl is6-halophenyl-2-(alkyl-4-isoxolylalkyl)-4,5-dihydropyridazinone.

Cycloalkylalkyl is, for example, (C₃ -C₆)cycloalkyl-(C₁ -C₆)alkyl suchas cyclopropylmethyl. Heterocyclyalkyl is, for example, heterocyclyl(C₁-C₆)alkyl such as 2,3-epoxypropyl or alkyl-2-furanylmethylene.Phenylalkyl is, for example, phenyl(C₁ -C₆)alkyl such as be benzyl or3-chlorobenzyl. Alkenyl is, for example, (C₃ -C₆)alkenyl such as2-butenyl, 3-methyl-2-butenyl or allenyl. Haloalkenyl is, for example,halo(C₃ -C₆)alkenyl such as 3-bromo-2-propenyl, 3,3-dibromo-2-propenylor 4-bromo-2-butenyl. Phenylalkenyl is, for example, phenyl(C₃-C₆)alkenyl such as 3-phenyl-2-propenyl. Alkynylalkenyl is, for example,(C₃ -C₆)alkynyl(C₂ -C₆)alkenyl such as3-(3-methyl-2-propynyl)-2-propenyl or 3-acetylenyl-2-propenyl. Alkynylis, for example, (C₃ -C₁₀)alkynyl or dialkynyl such as 2-propynyl,2-butynyl, 1-methyl-2-butynyl, 2-pentynyl, 1-methyl-2-pentynyl,3-vinyl-2-propynyl, 3-pentynyl, 4-methyl-2-pentynyl,5,5-dimethyl-2-pentynyl, 2-hexynyl, penta-2,4-diynyl, 2-octynyl or2-decynyl. Haloalkynyl is for example, halo(C₃ -C₆)alkynyl such as3-iodo-2-propynyl, 4-chloro-2-butynyl, 4-bromo-2-butynyl,4-fluoro-2-butynyl, 4,4-difluoro-2-butynyl, 5-fluoro-2-pentynyl or4-fluoro-2-pentynyl. Phenylalkynyl is, for example, phenyl(C₃ -C₆)alkynyl such as 3-phenyl-2-propynyl or 3-(4-chlorophenyl)-2-propynyl.Heterocyclylalkynyl is, for example, heterocyclyl (C₃ -C₆) alkynyl suchas 3-(2-thienyl)-2-propynyl. Cycloalkylalkynyl is, for example,3-cyclohexyl-2-propynyl or 4-cyclohexyl-2-butynyl. Alkenylalkynyl is,for example, (C₃ -C₆)alkenyl(C₃ -C₆)alkynyl such as3-(vinyl)-2-propynyl, 3-(2-methylvinyl)-2-propynyl or3-(2-propenyl)-2-propynyl. Hydroxyalkynyl is, for example, hydroxy(C₃-C₆)alkynyl such as 5-hydroxy-2-pentynyl or 4-hydroxy-2-pentynyl.Alkoxyalkynyl is, for example, (C₁ -C₆)alkoxy(C₃ -C₆)alkynyl such as4-methoxy-2-pentynyl or 4,4-diethoxy-2-butynyl. Alkanoyloxyalkynyl is,for example, (C₁ -C₆)alkanoyloxy(C₃ -C₆)alkynyl such as4-acetyloxy-2-pentynyl. Formyalkynyl is, for example, formyl(C₃-C₆)alkynyl such as 3-formyl-2-propynyl. Trialkylsilylalkynyl is, forexample tri(C₁ -C₆)alkylsilyl(C₃ -C₆) alkynyl such as3-trimethylsilyl-2-propynyl. Trialkyltinalkynyl is, for example, tri(C₁-C₆)alkyltin(C₃ -C₆)alkynyl such as 3-(tri-n-butyltin)-2-propynyl.Haloalkenylalkynyl is, for example, halo(C₃ -C₆)alkenyl(C₃ -C₆)alkynylsuch as 3-(1,2,2-trifluorovinyl)-2-propynyl. Carboxyalkynyl is, forexample, carboxy(C₃ -C₆)alkynyl such as 3-carboxy-2-propynyl.Alkoxycarbonylalkynyl is, for example, (C₁ -C₆)alkoxycarbonyl-(C₃-C₆)alkynyl such as 3-(methoxycarbonyl)-2-propynyl and the like.

R² and R³ can be linked together to form a (C₁ -C₃)alkyl, (C₂-C₃)alkylene or carbonyl link which can be, for example, a relativelysimple linear chain link, such as in 4,4a,5,6-tetrahydro-8-haloh!-cinnolin-2-R¹ -3-one or the 5,6-dihydro form thereof. R² and R³ canbe linked together in a (C₁ -C₃)alkyl, (C₂ -C₃)alkylene or carbonyl linkother than a simple linear chain, such as the fused ring structureexemplified by 8-R'-acenaphtho- 1,2c!pyridazin-9-one.

R² and R⁷ can be linked together to form a fused phenyl ring.

The term "heterocyclyl" includes five- and six-membered aromatic,partially saturated or saturated rings or bicyclic ring systemscontaining up to 10 atoms containing one hetero atom selected from thegroup of oxygen, sulfur, or nitrogen. Examples include thienyl, epoxy,benzothienyl, pyridyl, quinolyl and the like.

Further, in accordance with the present invention, there are providedcompositions containing the above described compounds of the instantinvention. In addition, many of the compounds useful in this inventionare novel. The compounds which are new include compounds wherein R¹ isalkynyl or substituted alkynyl.

In an embodiment of the invention the compounds which are useful havethe structure ##STR4## wherein A is --(CHR²)_(n) --CHR⁷ --Z--;

--CR² ═CR⁷ --Z--;

--CR² ═N--Z--;

--CHR² --CR⁷ ═Y--; or

--CR² ═CR² --Y═;

D is CR⁸ or nitrogen;

Q is an aromatic group selected from ##STR5## Z is carbonyl (C═O) orthiocarbonyl (C═S); Y is carbon substituted by halo, (C₁ -C₆)alkoxy, (C₃-C₆)alkynylthio or triazolyl;

wherein

R¹ is (C₁ -C₆) straight or branched alkyl, hydroxy(C₁ -C₆)alkyl,cyano(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkylalkyI, (C₁ -C₆)alkyl,heterocyclyl(C₁ -C₆)alkyl, phenyl, phenyl(C₁ -C₆)alkyl, (C₃ -C₆)alkenyl,halo(C₃ -C₆)alkenyl, phenyl(C₃ -C₆)alkenyl, (C₃ -C₆)alkynyl(C₂-C₆)alkenyl, (C₃ -C₁₀)alkynyl, (C₄ -C₂₀)dialkynyl, halo(C₃ -C₆)alkynyl,phenyl(C₃ -C₆)alkynyl, heterocyclyl(C₃ -C₆)alkynyl, (C₃-C₆)cycloalkyl(C₃ -C₆)alkynyl, (C₃ -C₆) alkenyl(C₃ -C₆ )alkynyl,hydroxy(C₃ -C₆ )alkynyl, (C₁ -C₆ )alkoxy(C₃ -C₆ ) alkynyl, (C₁-C₆)alkanoyloxy(C₃ -C₆)alkynyl, formyl(C₃ -C₆)alkynyl, tri-(C₁-C₆)alkylsilyl(C₃ -C₆)alkynyl, tri(C₁ -C₆)alkyltin(C₃ -C₆)alkynyl,halo(C₃ -C₆)alkenyl(C₃ -C₆)alkynyl, carboxy(C₃ -C₆)alkynyl, or (C₁-C₆)alkoxycarbonyl(C₃ -C₆)alkynyl.

R⁷ can be hydrogen, (C₁ -C₃)alkyl, phenyl, cyano, halogen, (C₃-C₁₀)alkynyl, (C₃ -C₆)alkynyl(C₂ -C₆)alkenyl, (C₄ -C₂₀)dialkynyl,halo(C₃ -C₆)alkynyl, or (C₃ -C₆)alkenyl(C₃ -C₆)alkynyl;

R⁸ is hydrogen, (C₁ -C₃)alkyl, phenyl, cyano or halogen;

R³ and R⁶ are independently hydrogen, or halogen

R⁴ is hydrogen, halogen, (C₁ -C₆)alkoxy or nitro;

R⁵ is hydrogen, halogen, nitro, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁ -C₆)alkylthio, halo(C₁ -C₆)alkyl, halo(C₁ -C₆)alkoxy, halo(C₁ -C₆)alkylthio,phenyl, phenoxy or cyano; or

R² and R³ together form a (C₁ -C₃)alkyl, (C₂ -C₃)alkylene or carbonyllink; or

R² and R⁷ together form a fused phenyl ring;

X is oxygen (O) or sulfur (S); and

n is 0, 1 or 2; and

agronomically acceptable salts thereof.

In a more preferred embodiment of the invention the compound used havethe formula ##STR6## wherein R¹ is (C₁ -C₆) straight or branched alkyl,hydroxy(C₁ -C₆)alkyl, cyano(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁ -C₆)alkyl, phenyl, phenyl(C₁ -C₆)alkyl, (C₃-C₆)alkenyl, halo(C₃ -C₆)alkenyl, phenyl(C₃ -C₆)alkenyl, (C₃-C₆)alkynyl(C₂ -C₆)alkenyl, (C₃ -C₁₀)alkynyl, (C₄ -C₂₀)dialkynyl,halo(C₃ -C₆)alkynyl, phenyl(C₃ -C₆)alkynyl, heterocyclyl(C₃ -C₆)alkynyl,(C₃ -C₆)cycloalkyl(C₃ -C₆)alkynyl, (C₃ -C₆)alkenyl(C₃ -C₆)alkynyl,hydroxy(C₃ -C₆)alkynyl, (C₁ -C₆)alkoxy(C₃ -C₆)alkynyl, (C₁-C₆)alkanoyloxy(C₃ -C₆)alkynyl, formyl(C₃ -C₆)alkynyl, tri(C₁-C₆)alkylsilyl(C₃ -C₆)alkynyl, tri(C₁ -C₆)alkyltin(C₃ -C₆ )alkynyl,halo(C₃ -C₆)alkenyl(C₃ -C₆)alkynyl, carboxy(C₃ -C₆)alkynyl, or (C₁-C₆)alkoxycarbonyl(C₃ -C₆)alkynyl. R² is hydrogen or (C₁ -C₆)alkyl;

R³ is hydrogen, halogen, (C₁ -C₆)alkyl, or (C₁ -C₆)alkoxy; or

R² and R³ together form a (C₁ -C₃)alkyl, (C₂ -C₃)alkenyl or carbonyllink;

R⁴ is hydrogen, (C₁ -C₆)alkyl, halogen or nitro;

R⁵ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, phenoxy, halo(C₁-C₆)alkyl; (C₁ -C₆)alkylthio, cyano, phenyl, halo(C₁ -C₆)alkoxy orhalogen;

R⁶ is hydrogen or halogen; and

R⁷ is hydrogen, (C₁ -C₆)alkyl, phenyl or halogen, (C₃ -C₁₀)alkynyl, (C₃-C₆)alkynyl(C₂ -C₆)alkenyl, (C₄ -C₂₀)dialkynyl, halo(C₃ -C₆)alkynyl, or(C₃ -C₆)alkenyl(C₃ -C₆)alkynyl;

and agronomically acceptable salts thereof.

More preferred are compounds wherein

R¹ is (C₃ -C₁₀)alkynyl, (C₃ -C₆)alkenyl, (C₃ -C₆)alkenyl(C₃ -C₆)alkynylor (C₃ -C₆)alkynyl(C₃ -C₆)alkenyl;

R² is hydrogen or (C₁ -C₆)alkyl;

R³ is hydrogen, halo or (C₁ -C₆)alkoxy;

R² and R³ together form a (C₁ -C₃)alkyl, (C₂ -C₃)alkenyl or carbonyllink;

R⁴ is hydrogen, halo or (C₁ -C₆)alkyl;

R⁵ is hydrogen, halo or halo(C₁ -C₆)alkoxy;

R⁶ is hydrogen or fluoro; and

R⁷ is hydrogen.

Even more preferred compounds of this embodiment are compounds whereinR¹ is 2-pentynyl, 2-hexynyl, 3-vinyl-2-propynyl, 4-fluoro-2-pentynyl,5-fluoro-2-pentynyl, or 3-(1-propenyl)-2-propynyl, R² is hydrogen, R³ ishydrogen, R² and R³ can together form a (C₁ -C₃)alkyl link;

R⁴ is hydrogen, methyl, chloro or fluoro, R⁵ is chloro, fluoro, bromo ortrifluoromethoxy, R⁶ is hydrogen or fluoro and R⁷ is hydrogen.

Preferred compounds where R¹ is 2-pentynyl are those in which R², R³, R⁶and R⁷ are hydrogen, R⁵ is chloro and R⁴ is hydrogen or fluoro.

In a second preferred embodiment are compounds of the structure ##STR7##wherein R¹ is (C₃ -C₆)alkynyl, (C₂ -C₆)alkynyl(C₃ -C₆)alkynyl, halo(C₃-C₆) alkynyl;

R² is hydrogen or halogen;

R³ is hydrogen or (C₁ -C₆)alkyl; or

R² and R³ together form a (C₁ -C₃)alkyl, (C₂ -C₃)alkenyl or carbonyllink;

R⁴ is hydrogen, halogen or (C₁ -C₆)alkyl;

R⁵ is hydrogen, halogen, (C₁ -C₆)alkyl; or (C₁ -C₆)alkoxy;

R⁶ is hydrogen or halogen; and

R⁷ is hydrogen or halogen; and

agronomically acceptable salts thereof.

More preferred compounds of this embodiment are compounds

wherein

R¹ is (C₃ -C₆)alkynyl;

R² is hydrogen or halo;

R² and R³ together form a (C₁ -C₃)alkyl link;

R³ is hydrogen or (C₁ -C₆)alkyl;

R⁴ is hydrogen, halo or (C₁ -C₆)alkyl;

R⁵ is hydrogen, halo, (C₁ -C₆)alkyl, or (C₁ -C₆)alkoxy;

R⁶ is hydrogen or fluoro; and

R⁷ is hydrogen or fluoro.

Even more preferred are compounds wherein R¹ is 2-pentynyl,4-fluoro-2-pentynyl, 3-vinyl-2-propynyl, or 5-fluoro-2-pentynyl, R² ishydrogen, R³ is hydrogen, R² and R³ together form a (C₁ -C₃)alkyl link;R⁴ is hydrogen, fluoro or chloro, R⁵ is fluoro, chloro or bromo, R⁶ ishydrogen, and R⁷ is hydrogen.

Preferred are compounds wherein R¹ is 2-pentynyl; R², R³, R⁶ and R⁷ arehydrogen; R⁴ is hydrogen or fluoro and R⁵ is chloro.

Certain compounds which are useful in the method of the instantinvention are known and commercially available. However, they have notpreviously been disclosed to be active against Pyricularia oryzae andthus they have not been disclosed to be active in the method of theinstant invention. These compounds include compounds 1-5 listed in TableI below.

The dihydropyridazinones compounds of the instant invention areprepared, for example, by a two-step sequence starting from an arylketoadd or ester of the formula ##STR8## wherein Q is as defined in FormulaI above and R^(a) is hydrogen or alkyl. Compound II is reacted withabout an equivalent of hydrazine or a substituted hydrazine having theformula

    H.sub.2 NNHR.sup.b                                         III

wherein R^(b) is hydrogen to yield a compound having the formula##STR9##

Examples of suitable solvents for this reaction include alcohols, suchas ethanol, n-propanol or n-butanol. The reaction is generally carriedout at about atmospheric pressure at a temperature of from about -10° C.to about 200° C. Preferably, the temperature employed is in the range offrom about 25° C. to about 150° C., more preferably from about 50° C. toabout 125° C.

The compound of Formula IV wherein R^(b) is hydrogen is then alkylatedusing the appropriate alkylating agent, for example an alkynyl mesylateor alkynyl halide, by a standard N-alkylation procedure, for example,using sodium hydride in an aprotic polar solvent such asdimethylformamide (DMF) or by using a phase transfer catalyst such astetrabutylammonium hydrogen sulfate to obtain the desireddihydropyridazinone (formula IV wherein R^(b) is not hydrogen) of theinstant invention. The reaction is generally carried out at atemperature of from about -10° C. to about 250° C. More preferably, thereaction is carried out at a temperature of from about 20° C. to about100° C.

The dihydropyridazinone of Formula IV wherein R^(b) is hydrogen can beconverted to the corresponding pyridazinone of the invention, forexample, by bromine oxidation. The reaction is generally carried out inan organic acid solvent such as acetic acid at a temperature of fromabout 0° C. to about 150° C. More preferably, the temperature rangesfrom about 20° C. to about 100° C., more particularly from about 50° C.to about 75° C.

The starting arylketoacids can be obtained from commercial sources orprepared by procedures known in the literature such as 1) Friedel-Craftsacylation of aromatic compounds with succinic anhydride, 2) a malonicester condensation (the preparation ofbis-(di-t-butyl-carboxy)ethylcarboxyethane from di-t-butylmalonate,acylation with an aromatic acyl chloride and decarboxylation of theketotriester) or 3) a Claisen condensation.

Typically, the alkynyl mesylates and alkynyl halides used in thealkylation step of the procedure are prepared by means known in the art,for example:

a) from commercially available alcohols ##STR10## b) from commerciallyavailable alkynes ##STR11## c) from propargyl chloride ##STR12## whereinR⁷ is alkyl, cycloalkyl, etc. and R is, for example, alkyl.

Additionally, the alkynyl group can be modified after the alkylationstep has taken place, for example by treatment with diethylaminosulfurtrifluoride (DAST), acetic anhydride, alcohol/hydrogen chloride to addfluorine, acetyl or an alkoxy group to the carbon alpha to the alkynylor treatment with a haloalkene in the presence ofbis(triphenylphosphine)palladium dichloride, copper(I) iodide andtriethylamine to add an alkenyl group to the alpha carbon of the alkyne:##STR13##

The pyridinones are prepared, for example, by cyclization of2-aryldialkylamino propenals (V) and a cyanoacetamide (VI) in thepresence of base to yield the corresponding 3-cyano-5-aryl-pyridinone(VII) ##STR14## which is then hydrolyzed and decarboxylated to yield thepyridinone (VIII). ##STR15## The pyridinone is alkylated as describedabove for the dihydropyridazinones to yield compounds of the invention.

Examples of suitable solvents for the cyclization reaction includealcohols, such as methanol or ethanol. Examples of suitable basesinclude sodium methoxide and sodium ethoxide. The reaction is generallycarried out at about atmospheric pressure at a temperature of from about25° C. to about 250° C. Preferably, the temperature employed is in therange of from about 50° C. to about 200° C., more preferably from about100° C. to about 150° C.

The hydrolysis and decarboxylation step is typically carried out in astrong acid such as 85% H₃ PO₄ or concentrated sulfuric acid atatmospheric pressure at temperatures between 50° and 200° C., preferablybetween 100°-150° C.

The starting pyrimidinones (IX) of the invention can be made by##STR16## cyclizing 2-aryl dialkylamino propenals (V) with urea in thepresence of acid. Preferred acids are mineral acids such as hydrochloricacid. Preferred solvents are polar solvents, for example alcohols suchas ethanol. The reaction is preferably carried out at atmosphericpressure at a temperature between 20° and 200° C., more preferablybetween 50° and 150° C. The alkylation is then carried out as describedabove for the dihydropyridazinones.

The starting oxadiazin-2-ones (X) of the invention can be prepared##STR17## by reacting an α-hydroxy acetophenone (XI) with ethylcarbazate (XII) in ##STR18## a polar solvent, for example, an alcoholsuch as ethanol preferably at a temperature between 0° and 150° C., morepreferably between 15° and 70° C. to obtain compound XIII which is thencyclized in a polar solvent, for example, an alcohol such as ethanol, inthe presence of base such as sodium hydride to yield the oxadiazin-2-one(X). Alkylation as described above for the dihydropyridazinones yieldscompounds of the instant invention.

The starting oxadiazin-5-ones (XIV) can be prepared by reacting a##STR19## substituted benzoic hydrazide (XV) with a haloacetyl chloride(XVI) in ##STR20## an aprotic solvent such as dioxane, tetrahydrofuran,glyme or other poylether, preferably at a temperature between 0° and150° C., more preferably between 50° and 100° C. to obtain compound XVIIwhich is subsequently cyclized in the presence of a base such as sodiumhydroxide to yield the oxadiazin-5-one (XIV). Alkylation as describedabove for the dihydropyridazinones yields compounds of the instantinvention.

The starting thiadiazin-2-ones (XVIII) can be prepared by reacting a##STR21## phenacyl halide (XIX), preferably a phenacyl bromide, with analkoxythiocarbonyl hydrazine (XX) such as methyl thiocarbazate in a##STR22## polar solvent such as acetonitrile, dimethylformamide or analcohol, more preferably acetonitrile, preferably at a temperaturebetween 0° and 150° C., more preferably between 50° and 100° C. toobtain compound XVIII. Alkylation as described above for thedihydropyridazinones yields compounds of the instant invention.

The starting indenopyridazinones (XXI), wherein R⁸ is hydrogen or##STR23## (C₁ -C₆)alkyl, can be prepared by carboxymethylating theappropriate indanone (XXII) using an agent such as dimethylcarbonate inthe presence of base such as sodium hydride and an aprotic solvent suchas dimethoxyethane, followed by alkylation with an agent such as ethylbromoacetate in the presence of base such as sodium hydride and anaprotic solvent such as dimethylformamide to obtain the diester (XXIII).##STR24## The diester is subsequently decarboxylated and hydrolyzedusing standard procedures, preferably heating in a aqueous acidsolution, more preferably, refluxing in aqueous hydrochloric acid toobtain the corresponding ketoacid (XXIV) which is cyclized and alkylatedas described above ##STR25## for the dihydropyridazinones to yieldcompounds of the instant invention.

The following examples will further illustrate this invention, but arenot intended to limit it in any way. In Tables I to III examples ofcompounds of the invention are listed. For compounds that are new,elemental analyses are listed in Table IV or proton NMR data is listedin Table V. Specific illustrative preparations of the compounds aredescribed after Table V.

                                      TABLE I                                     __________________________________________________________________________     ##STR26##                                                                    Compound                                                                      Number                                                                              R.sup.1         R.sup.2                                                                          R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                            R.sup.6                                                                         R.sup.7                               __________________________________________________________________________     1.   CH.sub.2 C CCH.sub.3                                                                          H  H   H   Cl   H H                                      2.   (CH.sub.2).sub.3 OH                                                                           H  H   H   OCH.sub.3                                                                          H H                                      3.   CH.sub.2 CH(OH)CH.sub.2 CH.sub.3                                                              H  H   Cl  Cl   H H                                      4.   CH.sub.2 CH(OH)CH.sub.2 CH.sub.3                                                              H  H   H   Cl   H H                                      5.   (CH.sub.2).sub.3 OH                                                                           H  H   Cl  Cl   H H                                      6.   CH.sub.2 C CH   H  H   H   Cl   H H                                      7.   (CH.sub.2).sub.3 CH.sub.3                                                                     H  H   H   Cl   H H                                      8.   CH.sub.2 CHCHCH.sub.3                                                                         H  H   H   Cl   H H                                      9.   CH.sub.2 C CCH.sub.3                                                                          H  H   H   H    H H                                      10.  CH.sub.2 C.sub.6 H.sub.5                                                                      H  H   H   Cl   H H                                      11.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   OCH.sub.3                                                                          H H                                      12.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   Cl   H H                                      13.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   F    H H                                      14.  C.sub.6 H.sub.5 H  H   H   Cl   H H                                      15.  C(CH.sub.3).sub.3                                                                             H  H   H   Cl   H H                                      16.  C(O)C.sub.6 H.sub.5                                                                           H  H   H   Cl   H H                                      17.  CH.sub.2 C CC.sub.6 H.sub.5                                                                   H  H   H   Cl   H H                                      18.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   CH.sub.3                                                                           H H                                      19.  CH.sub.2 C CCH.sub.3                                                                          H  Cl  H   Cl   H H                                      20.  CH.sub.2 C CCH.sub.3                                                                          H  H   F   OCH.sub.3                                                                          H H                                      21.  CH.sub.2 CH.sub.2 C CCH.sub.3                                                                 H  H   H   Cl   H H                                      22.  CH(CH.sub.3)C CCH.sub.3                                                                       H  H   H   Cl   H H                                      23.  CH.sub.2 C CCH.sub.3                                                                          H  H   Cl  Cl   H H                                      25.                                                                                 ##STR27##      H  H   H   Cl   H H                                      26.  CH.sub.2 C CCH.sub.3                                                                          CH.sub.3                                                                         H   H   Cl   H H                                      27.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   Cl   H CH.sub.3                               28.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Cl  Cl   H H                                      29.  CH.sub.2 C CCH.sub.2 CH.sub.2 CH.sub.3                                                        H  H   H   Cl   H H                                      30.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   H    H C.sub.6 H.sub.5                        31.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   Br   H H                                      32.  CH.sub.2 CHC(CH.sub.3).sub.2                                                                  H  H   H   Cl   H H                                      33.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   OC.sub.6 H.sub.5                                                                   H H                                      34.  CH.sub.2 C CCH(CH.sub.3).sub.2                                                                H  H   H   Cl   H H                                      35.  CH.sub.2 CN     H  H   H   Cl   H H                                      36.                                                                                 ##STR28##      H  H   H   Cl   H H                                      37.  CH.sub.2 C CCH.sub.3                                                                          H  H   Cl  H    H H                                      38.  CH.sub.2 C CCH.sub.3                                                                          H  H   Cl  H    Cl                                                                              H                                      39.  CH.sub.2 C CCH.sub.3                                                                          H  H   N   Cl   H H                                      40.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   N   Cl   H H                                      41.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   CF.sub.3                                                                           H H                                      42.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   CF.sub.3                                                                           H H                                      43.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  Cl  Cl  CH.sub.3                                                                           Cl                                                                              H                                      44.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Cl  CH.sub.3                                                                           Cl                                                                              H                                      45.  CH.sub.2 C CC(CH.sub.3)CH.sub.2                                                               H  H   H   Cl   H H                                      46.  CH.sub.2 C CC(CH.sub.3).sub.3                                                                 H  H   H   Cl   H H                                      47.  CH.sub.2 C CCH(CH.sub.3)OH                                                                    H  H   H   Cl   H H                                      48.  CH.sub.2 C CCH(CH.sub.3)OCH.sub.3                                                             H  H   H   Cl   H H                                      49.  CH.sub.2 C CCH(CH.sub.3)OC(O)CH.sub.3                                                         H  H   H   Cl   H H                                      50.  CH.sub.2 C CCH.sub.2 CH.sub.2 OH                                                              H  H   H   Cl   H H                                      51.  CH.sub.2 C CCH.sub.2 CH.sub.2 F                                                               H  H   H   F    H H                                      52.  CHCCH.sub.2     H  H   H   Cl   H H                                      53.  CH.sub.2 C CCHFCH.sub.3                                                                       H  H   H   Cl   H H                                      54.  CH.sub.2 C CCOOH                                                                              H  H   H   Cl   H H                                      55.  CH.sub.2 C CCOOCH.sub.3                                                                       H  H   H   Cl   H H                                      56.  CH.sub.2 C CCHCH.sub.2                                                                        H  H   H   Cl   H H                                      57.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   C(CH.sub.3).sub.3                                                                  H H                                      58.  CH.sub.2 C CCH.sub.3                                                                          H  H   H   CH.sub.2 CH.sub.3                                                                  H H                                      59.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   CH.sub.2 CH.sub.3                                                                  H H                                      60.  CH.sub.2 C Cl   H  H   H   Cl   H H                                      61.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   SCH.sub.3                                                                          H H                                      62.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CH.sub.3                                                                          Cl   H H                                      63.  CH.sub.2 C CCH.sub.3                                                                          H  H   CH.sub.3                                                                          Cl   H H                                      64.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   CN   H H                                      65.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   NO.sub.2                                                                           H H                                      66.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   OCH.sub.2 CH.sub.3                                                                 H H                                      67.                                                                                 ##STR29##      H  H   H   Cl   H H                                      68.  CH.sub.2 C CC.sub.6 H.sub.4 -4-Cl                                                             H  H   H   Cl   H H                                      69.  CH.sub.2 CHCHBr H  H   H   Cl   H H                                      70.  CH.sub.2 CHCHC CCH(CH.sub.3).sub.2                                                            H  H   H   Cl   H H                                      71.  CH.sub.2 C CCH.sub.2 Br                                                                       H  H   H   Cl   H H                                      72.  CH.sub.2 C CCH.sub.2 Cl                                                                       H  H   H   Cl   H H                                      73.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  F   H   Cl   H H                                      74.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   Cl   H H                                      75.  CH.sub.2 CH C(Br)CH.sub.2 Br                                                                  H  H   H   Cl   H H                                      76.  CH.sub.2 C CCH.sub.2 F                                                                        H  H   H   Cl   H H                                      77.                                                                                 ##STR30##      H  H   H   Cl   H H                                      78.  CH.sub.2 CC CCFCF.sub.2                                                                       H  H   H   Cl   H H                                      79.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   C.sub.6 H.sub.5                                                                    H H                                      80.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   CH.sub.3                                                                           H H                                      81.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   OCH.sub.3                                                                          H H                                      82.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   F    H H                                      83.  CH.sub.2 C CCH.sub.3                                                                          H  H   F   Cl   H H                                      84.  CH.sub.2 CHCHC CH                                                                             H  H   H   Cl   H H                                      85.  CH.sub.2 C C(CH.sub.2).sub.6 CH.sub.3                                                         H  H   H   Cl   H H                                      86.  CH.sub.2 C CCSi(CH.sub.3).sub.3                                                               H  H   H   Cl   H H                                      87.  CH.sub.2 C CCH(OCH.sub.2 CH.sub.3).sub.2                                                      H  H   H   Cl   H H                                      88.  CH.sub.2 C CCHO H  H   H   Cl   H H                                      89.  CH.sub.2 C CCHF.sub.2                                                                         H  H   H   Cl   H H                                      90.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   Cl   F H                                      91.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   Br   H H                                      92.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   OCF.sub.3                                                                          H H                                      93.  CH.sub.2 C CC CH                                                                              H  H   H   Cl   H H                                      94.                                                                                 ##STR31##      H  H   H   Cl   H H                                      95.                                                                                 ##STR32##      H  H   H   Cl   H H                                      96.  CH.sub.2 C C(CH.sub.2).sub.4 CH.sub.3                                                         H  H   H   Cl   H H                                      97.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   Br   H H                                      98.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   H    F H                                      99.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  OCH.sub.3                                                                         H   Cl   H H                                     100.  CH.sub.2 C CCHCH.sub.2                                                                        H  H   F   Cl   H H                                     101.  CH.sub.2 C CCHCHCH.sub.3                                                                      H  H   H   Cl   H H                                     102.  CH.sub.2 C CCHCHCH.sub.3 (cis)                                                                H  H   H   Cl   H H                                     103.  CH.sub.2 C CHCHCH.sub.3 (trans)                                                               H  H   H   Cl   H H                                     104.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Cl  F    H H                                     105.  CH.sub.2 C.sub.6 H.sub.5 -3Cl                                                                 H  H   H   Cl   H H                                     201   CH.sub.3        H  H   H   Cl   H H                                     203   CH.sub.3        H  H   H   Cl   H CH.sub.2 C CH.sub.2 CH.sub.3          207   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   H   OCH.sub.2 O                                                                          H                                     208   CH(CH.sub.3)C CCH.sub.2 CH.sub.3 H                                                            H  H   Cl  H    H H                                     209   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  F   H   H    H H                                     210   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  CH.sub.3                                                                          H   H    H H                                     211   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  Cl  H   H    H H                                     212   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  OCH.sub.3                                                                         H   H    H H                                     213   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CF.sub.3                                                                          H    H H                                     214   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   H    H H                                     215   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CH.sub.3                                                                          H    H H                                     216   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Cl  H    H H                                     217   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CN  H    H H                                     218   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CF.sub.3                                                                          H    H H                                     219   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   OCH.sub.3                                                                         H    H H                                     220   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   OCH.sub.3                                                                         CH.sub.3                                                                           H H                                     221   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Cl  OCH.sub.3                                                                          H H                                     222   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   Br  F    H H                                     223   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   NO.sub.2                                                                          OCH.sub.3                                                                          H H                                     224   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   F    H H                                     225   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   F   CH.sub.3                                                                           H H                                     226   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H  H   CH.sub.3                                                                          OCH.sub.3                                                                          H H                                     231                                                                                  ##STR33##      H  H   H   Cl   H H                                     233   CH.sub.2 CONHNH.sub.2                                                                         H  H   H   Cl   H H                                     234                                                                                  ##STR34##      H  H   H   Cl   H H                                     237                                                                                  ##STR35##      H  H   H   Cl   H H                                     238                                                                                  ##STR36##      H  H   H   Cl   H H                                     239                                                                                  ##STR37##      H  H   H   Cl   H H                                     240                                                                                  ##STR38##      H  H   H   Cl   H H                                     241                                                                                  ##STR39##      H  H   H   Cl   H H                                     __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR40##                                                                    Compound                                                                      Number                                                                              R.sup.1         R.sup.2                                                                             R.sup.3                                                                          R.sup.4                                                                          R.sup.5                                                                            R.sup.6                                                                         R.sup.7                              __________________________________________________________________________    108.  CH.sub.2 C CCH.sub.3                                                                          H     H  H  Cl   H H                                    109.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  H  Cl   H H                                    110.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  H  CH.sub.2 CH.sub.3                                                                  H H                                    111.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  H  C(CH.sub.3).sub.3                                                                  H H                                    112.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  Cl Cl   H H                                    113.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  CH.sub.3                                                                         Cl   H H                                    114.  CH.sub.2 C CCH.sub.3                                                                          H     H  CH.sub.3                                                                         Cl   H H                                    115.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     CH.sub.3                                                                         H  Cl   H H                                    116.  CH.sub.2 C CCH.sub.3                                                                          H     CH.sub.3                                                                         H  Cl   H H                                    117.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  H  OCH.sub.2 CH.sub.3                                                                 H H                                    118.  CH.sub.2 C CH   H     H  H  Cl   H H                                    119.  CH.sub.2 CH CHCH.sub.2                                                                        H     H  H  Cl   H H                                    120.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  F  Cl   H H                                    121.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  H  Br   H H                                    122.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 F     H  H  Cl   H F                                    123.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 F     H  H  Cl   H H                                    124.  CH.sub.2 C CSn(C.sub.4 H.sub.9 -n).sub.3 H                                                    H     H  Cl H    H H                                    125.  CH.sub.2 C CC CH                                                                              H     H  H  Cl   H H                                    126.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  F  H    F H                                    127.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  F  Br   H H                                    128.  CH.sub.2 C CCHCH.sub.2                                                                        H     H  F  Cl   H H                                    129.  CH.sub.2 C CCH.sub.2 CH.sub.3                                                                 H     H  Cl F    H H                                    130.  CH.sub.2 C CCHFCH.sub.3                                                                       H     H  H  Cl   H H                                    131.  CH.sub.2 C CCH.sub.2 CH.sub.2 F                                                               H     H  H  Cl   H H                                    204                                                                                  ##STR41##      H     H  H  Cl   H H                                    228   CH.sub.2 C CCH.sub.2 CH.sub.3                                                                  ##STR42##                                                                          H  H  H    H CN                                   __________________________________________________________________________

                  TABLE III                                                       ______________________________________                                         ##STR43##                                                                     ##STR44##                                                                     ##STR45##                                                                     ##STR46##                                                                     ##STR47##                                                                     ##STR48##                                                                     ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                     ##STR53##                                                                     ##STR54##                                                                     ##STR55##                                                                     ##STR56##                                                                     ##STR57##                                                                     ##STR58##                                                                     ##STR59##                                                                     ##STR60##                                                                     ##STR61##                                                                     ##STR62##                                                                     ##STR63##                                                                     ##STR64##                                                                     ##STR65##                                                                     ##STR66##                                                                     ##STR67##                                                                     ##STR68##                                                                     ##STR69##                                                                     ##STR70##                                                                     ##STR71##                                                                     ##STR72##                                                                     ##STR73##                                                                     ##STR74##                                                                     ##STR75##                                                                     ##STR76##                                                                     ##STR77##                                                                     ##STR78##                                                                     ##STR79##                                                                     ##STR80##                                                                     ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                    ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                        ELEMENTAL ANALYSES                                                            Cmpd     Calculated     Found                                                 No.      % C    % H      % N  % C    % H  % N                                 ______________________________________                                         6.      63.39  4.49     11.35                                                                              66.22  5.66 8.92                                 7.      63.51  6.47     10.58                                                                              63.84  6.88 8.92                                 8.      64.00  5.75     10.66                                                                              64.05  5.77 10.46                                10.     68.35  5.06     9.37 68.60  5.21 9.09                                 11.     70.29  6.29     10.92                                                                              70.21  6.55 9.97                                 12.     65.57  5.50     10.19                                                                              65.34  5.63 9.43                                 13.     68.87  5.41     11.50                                                                              68.63  5.29 11.24                                14.     67.49  4.57     9.84 67.66  4.53 9.68                                 15.     62.11  8.50     10.35                                                                              63.70  6.50 10.02                                16.     65.28  4.18     8.96 68.83  4.17 9.30                                 17.     70.69  4.68     8.68 68.42  4.70 7.53                                 18.     74.97  6.71     11.65                                                                              74.64  6.79 11.31                                19.     56.96  4.10     9.49 56.97  4.60 8.70                                 20.     65.68  5.51     10.11                                                                              64.69  5.52 10.06                                21.     65.57  5.50     10.20                                                                              65.29  5.30 10.36                                22.     65.57  5.50     10.20                                                                              65.25  5.22 10.16                                23.     56.95  4.07     9.45 57.19  4.18 9.16                                 24.     77.92  7.79     9.09 75.12  7.67 8.85                                 25.     64.00  5.75     10.66                                                                              63.75  5.67 10.96                                26.     65.57  5.50     10.20                                                                              63.70  5.47 9.68                                 27.     65.57  5.50     10.20                                                                              63.37  5.32 9.96                                 28.     58.27  4.56     9.06 58.58  4.55 8.82                                 29.     66.51  5.96     9.71 67.73  6.57 8.77                                 31.     55.00  4.26     9.18 57.92  5.39 8.05                                 32.     65.10  5.79     10.13                                                                              64.07  6.13 9.70                                 33.     75.45  5.69     8.80 74.64  5.59 8.77                                 34.     66.54  5.93     9.70 66.36  5.89 9.59                                 35.     58.19  4.07     16.96                                                                              58.05  4.15 16.68                                36.     59.11  4.30     9.19 58.88  4.16 8.80                                 37.     64.50  5.02     10.74                                                                              64.06  4.93 10.60                                38.     56.50  4.14     9.52 56.73  4.06 9.34                                 39.     54.99  3.93     9.17 55.70  3.90 14.03                                40.     56.34  4.38     8.76 56.70  4.38 13.85                                41.     62.34  4.87     9.09 62.35  4.84 9.06                                 42.     61.22  4.42     9.52 60.48  4.40 9.55                                 43.     53.71  4.20     7.83 52.45  4.11 7.56                                 44.     59.44  4.95     8.67 57.67  4.82 7.94                                 45.     67.01  5.27     9.76 67.32  5.37 8.94                                 46.     67.43  6.32     9.25 67.26  6.52 9.19                                 47.     61.96  5.20     9.63 61.93  5.56 8.67                                 48.     63.05  5.62     9.19 59.33  5.40 8.33                                 49.     64.45  5.41     8.84 59.73  5.27 7.73                                 52.     63.81  3.71     11.44                                                                              60.31  4.04 10.66                                54.     57.84  3.81     9.63 56.10  3.90 8.42                                 56.     66.06  4.80     10.27                                                                              64.52  4.79 10.15                                57.     77.03  8.11     9.46 76.30  8.12 9.59                                 58.     75.59  7.09     11.02                                                                              70.90  6.86 10.60                                59.     76.12  7.46     10.45                                                                              75.89  8.07 8.78                                 60.     41.88  2.68     7.52 32.86  2.39 6.25                                 61.     67.13  6.29     9.79 66.96  6.39 9.51                                 63.     65.57  5.46     10.20                                                                              67.67  6.35 9.11                                 64.     72.45  5.66     15.85                                                                              72.68  5.92 15.55                                65.     71.83  7.04     9.86 64.59  6.20 12.98                                66.     71.83  7.04     9.86 71.56  7.01 9.81                                 67.     62.09  3.98     8.52 61.21  3.95 8.47                                 68.     63.81  3.95     7.84 63.70  3.88 7.55                                 69.     47.66  3.69     8.55 48.89  3.89 8.33                                 70.     68.67  6.08     8.89 63.30  5.56 8.03                                 71.     49.51  3.56     8.24 48.20  3.35 7.50                                 72.     56.96  4.10     9.49 54.00  3.89 8.53                                 73.     61.54  4.79     9.57 63.47  5.59 8.54                                 75.     39.99  3.11     6.66 40.18  2.91 6.74                                 76.     60.33  4.34     10.00                                                                              59.18  4.13 9.61                                 77.     62.39  4.53     9.70 61.43  4.26 9.36                                 78.     55.14  3.08     8.57 53.96  2.90 8.35                                 80.     75.56  7.13     11.02                                                                              75.18  7.68 10.58                                81.     71.09  6.71     10.37                                                                              67.47  6.31 9.64                                 82.     69.75  5.85     10.85                                                                              70.53  6.22 10.09                                84.     66.06  4.80     10.27                                                                              64.48  4.69 9.76                                 85.     69.65  7.30     8.12 69.77  7.26 8.04                                 86.     60.26  6.00     8.78 60.15  5.95 8.70                                 87.     61.98  6.07     8.03 61.81  5.78 8.19                                 88.     61.21  4.03     10.19                                                                              60.73  4.06 9.70                                 89.     56.67  3.74     9.44 55.02  3.77 8.80                                 91.     56.44  4.80     8.78 58.76  5.39 7.55                                 94.     69.34  6.43     8.51 65.38  6.08 7.96                                 95.     70.00  6.76     7.81 67.27  6.56 7.80                                 96.     68.23  6.68     8.84 67.96  6.48 8.63                                100.     61.97  4.16     9.63 61.19  3.99 9.48                                106.     51.96  3.19     8.08 53.49  3.43 7.63                                107.     67.01  5.27     9.76 64.76  5.20 9.27                                108.     64.99  4.26     10.83                                                                              64.72  4.17 10.68                               109.     62.83  4.54     9.77 65.73  4.82 10.21                               110.     76.79  6.77     10.53                                                                              75.75  6.92 9.50                                111.     77.55  7.48     9.52 72.95  7.68 7.66                                112.     58.63  3.91     9.12 58.44  4.04 8.97                                113.     67.02  5.24     9.77 69.13  6.38 8.21                                114.     66.06  4.77     10.28                                                                              64.29  5.04 9.92                                115.     67.02  5.24     9.77 66.91  5.30 9.77                                116.     66.09  4.77     10.28                                                                              65.85  4.94 9.99                                117.     72.36  6.43     9.92 66.42  5.51 6.52                                118.     63.81  3.70     11.45                                                                              63.81  3.62 11.39                               119.     66.55  4.09     10.34                                                                              64.70  3.84 10.13                               125.     67.04  3.37     10.42                                                                              63.56  3.31 9.20                                128.     62.40  3.49     7.70 62.36  3.29 9.51                                132.     68.70  5.77     18.79                                                                              68.12  5.98 17.84                               136.     78.62  6.21     9.66 78.54  6.12 9.43                                137.     71.41  5.98     8.32 70.25  5.88 8.04                                139.     74.96  6.71     11.65                                                                              72.83  6.68 10.70                               140.     62.04  5.21     12.06                                                                              61.01  5.04 12.28                               141.     82.26  5.18     7.99 77.90  5.27 7.02                                142.     76.26  6.39     11.10                                                                              74.32  6.45 11.49                               143.     67.01  5.27     9.76 64.82  4.99 9.72                                144.     69.74  5.47     9.57 68.27  5.48 8.92                                145.     70.72  5.16     5.16 69.34  5.21 4.86                                146.     68.80  4.30     9.44 64.41  4.12 9.16                                147.     45.03  2.87     6.18 55.13  3.54 7.20                                148.     69.39  4.76     9.52 64.21  4.61 8.37                                149.     66.07  4.77     10.28                                                                              67.34  5.51 5.57                                150.     68.45  4.89     5.70 66.62  4.87 5.46                                151.     71.89  5.46     7.98 70.88  4.94 7.83                                152.     62.38  4.53     9.70 61.00  4.41 9.12                                153.     61.95  5.20     9.63 60.77  5.06 9.10                                154.     70.70  4.68     8.68 70.27  4.36 8.54                                155.     67.88  5.70     9.31 68.06  5.50 8.83                                156.     67.49  4.60     9.83 68.27  4.48 9.17                                ______________________________________                                    

                  TABLE V                                                         ______________________________________                                        NMR DATA                                                                                     (200 MHz, delta scale in ppm,                                  Ex. No.                                                                             Solvent  Tetramethylsilane (TMS) standard)                              ______________________________________                                         9.   CDCl.sub.3                                                                             1.9(s, 3H); 2.6(t, 2H); 3.0(t, 2H); 4.6(s, 2H);                               7.4(m, 3H); 7.8(m, 2H)                                          30.  CDCl.sub.3                                                                             0.9(d, 2H); 4.7(s, 2H); 7-8(m, 10H)                             50.  CDCl.sub.3                                                                             2.5(t, 2H); 2.65(t, 2H); 2.95(t, 2H);                                         4.6(s, 2H); 7.4(d, 2H); 7.75(d, 2H)                             51.  CDCl.sub.3                                                                             2.5(t, 2H); 2.65(t, 2H); 2.95(t, 2H); 3.69(m, 1H);                            4.4(m, 1H); 4.6(s, 2H); 7.75(d, 2H)                             53.  CDCl.sub.3                                                                             1.6(dd, 3H); 2.65(t, 2H); 2.95(t, 2H); 4.7(s, 2H);                            5.75(m, 1H); 7.4(d, 2H); 7.75(d, 2H)                            55.  CDCl.sub.3                                                                             2.65(t, 2H); 2.95(t, 2H); 3.75(s, 3H); 4.7(s, 2H);                            7.4(d, 2H); 7.7(d, 2H)                                          62.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 2.4(s, 3H); 2.6(t.3H);                                2.95(t, 3H); 4.6(s, 2H); 7.4(d, 1H); 7.55(d, 1H);                             7.7(s, 1H)                                                      74.  CDCl.sub.3                                                                             1.1(t, H3); 2.2(q, 2H); 2.5(t, 2H); 2.95(t, 2H);                              4.55(s, 2H); 7.3-7.7(m, 3H)                                     79.  CDCl.sub.3                                                                             1.1(m, 3H); 2.2(m, 2H); 2.65(t, 2H); 3.05(t, 2H);                             4.65(bs, 2H); 7.4-8(m, 9H)                                      90.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 2.6(t, 2H); 3.0(t, 2H);                               4.6(s, 2H); 7.4(d, 2H)                                          92.  CDCl.sub.3                                                                             1.1(t, 3H); 2.15(q, 2H); 2.6(t, 2H); 2.95(t, 2H);                             4.6(s, 2H); 6.6(t, 1H); 7.3(t, 1H); 7.5(d, 1H);                               7.7(d, 1H)                                                      93.  CDCl.sub.3                                                                             2.0(s, 1H); 2.6(t, 2H); 2.9(t, 2H); 4.6(s, 2H);                               7.4(d, 2H); 7.8(d, 2H)                                          97.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 2.6(t, 2H); 2.95(t, 2H);                              4.5(s, 2H); 7.4-7.8(m, 3H)                                      98.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 2.65(t, 2H), 2.95(s, 2H);                             4.5(s, 2H); 6.8-7.3(m, 3H)                                      99.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 2.5(t, 2H); 2.9(t, 2H);                               3.9(s, 3H); 4.6(s, 2H); 7.0(d, 2H); 7.45(d, 2H)                101.  CDCl.sub.3                                                                             1.8(dd3H); 2.6(t, 2H); 2.9(t, 2H); 4.8(d, 2H);                                5.5(m, 1H); 6.1(m, 1H); 7.4(d, 2H); 7.7(d, 2H)                 102.  CDCl.sub.3                                                                             1.9(d, 3H); 2.6(t, 2H); 2.9(t, 2H); 4.8(s, 2H);                               5.5(d, 1H); 6.0(m, 1H); 7.4(d, 2H); 7.7(d, 2H)                 103.  CDCl.sub.3                                                                             1.8(d, 3); 2.6(t, 2); 2.9(t, 2); 4.7(s, 2); 5.5(d, 2);                        6.2(m, 1); 7.4(d, 2); 7.7(d, 2)                                104.  acetone-d.sub.6                                                                        1.1 (t, 3H); 2.1(q, 2H); 2.65(t, 2H); 3.0(t, 2H);                             4.5(s, 2H); 7.2-7.8(m, 3H)                                     105.  CDCl.sub.3                                                                             2.6(t, 2H); 3.0(t, 2H); 5.0(s, 2H); 7.4(m, 6H);                               7.9(d, 2H)                                                     115.  CDCl.sub.3                                                                             1.0(t, 2H); 1.2(t, 2H); 1.5(t, 2H); 2.2(m, 3H);                               3.0(m, 3H); 4.2(q, 3H); 6.0(m, 2H); 7-7.6(m, 4H)               120.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 5.0(s, 2H); 7.05(d, 1H);                              7.5(d, 1H); 7.55(s, 1H); 7.6(d, 1H); 7.65(d, 1H)               121.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 4.95(s, 2H); 7.05(d, 1H);                             7.5-7.8(m, 5H)                                                 122.  CDCl.sub.3                                                                             1.2(t, 3H); 2.2(q, 2H); 5.0(s, 2H); 7.5(d, 2H);                               7.8(d, 2H)                                                     123.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 4.9(s, 2H); 7.1(s, 1H);                               7.4(d, 2H); 7.8(d, 2H)                                         124.  CDCl.sub.3                                                                             0.9(t, 9H); 1.0(q, 6H); 1.2(q, 6H); 1.5(q, 6H);                               5.0(s, 2H); 7.0(d, 1H); 7.4(d, 2H); 7.7(d, 2H)                                7.8(d, 2H)                                                     126.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 5.0(s, 2H); 6.8-7.0(m, 1H);                           7.37.5(m, 2H); 7.7(d, 1H)                                      127.  acetone-d.sub.6                                                                        1.1(t, 3H), 2.2(q, 2H), 4.9(s, 2H), 7.0(d, 1H),                               7.7-7.9(m, 3H), 8.1(d, 1H)                                     129.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 5.0(s, 2H); 7.0(d, 1H);                               7.25(t, 1H); 7.7(dd, 2H); 8.0(d, 1H)                           130.  CDCl.sub.3                                                                             1.6(dd, 3H), 5.1(m, 2H), 5.15(m, 1/2H),                                       5.4(m, 1/2H), 7.1(d, 1H), 7.5(d, 2H), 7.7(d, 1H),                             7.8(d, 2H)                                                     131.  CDCl.sub.3                                                                             2.65(m, 2H), 4.4(t, 1H), 4.6(t, 1H), 5(m, 2H),                                7.0(d, 1H), 7.5(d, 2H), 7.7(d, 1H), 7.8(d, 2H)                 133.  CDCl.sub.3                                                                             1.8(t, 3H); 2.7(t, 2H); 3.15(t, 2H); 4.6(s, 2H);                              8.45(d, 2H); 9.3(d, 2H)                                        134.  CDCl.sub.3                                                                             1.9(s, 3H); 2.78(t, 2H); 3.18(t, 2H); 4.65(d, 2H);                            7-8.3(m, 7H)                                                   135.  CDCl.sub.3                                                                             1.9(s, 3H); 2.6(t, 2H); 3.25(t, 2H); 4.65(s, 2H);                             7.8(m, 7H)                                                     138.  CDCl.sub.3                                                                             1.8(t, 3H), 2.8(t, 2H), 3.25(t, 2H), 3.9(s, 2H),                              3.95(s, 3H), 4.7(s, 2H), 7.1(m, 3H), 7.7(m, 2H)                157.  CDCl.sub.3                                                                             1.1(1, 3H); 2.2(m, 2H); 3.5(s, 2H); 4.7(s, 2H);                               7.3(d, 2H) 7.8(d, 2H); 9.9(s, 1H)                              158.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 3.5(s, 2H); 4.1(s, 3H);                               4.6(s, 2H); 7.4(d, 2H); 7.8 (d, 2H); 9.8(s, 2H)                159.  CDCl.sub.3                                                                             1.1(t, 3H); 2.1(m, 2H); 3.5(s, 2H); 4.4(s, 2H);                               7.4(d, 2H); 7.8(d, 2H); 8.3(s, 1H); 8.5(s, 1H)                 160.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 3.5(s, 2H); 4.7(s, 2H);                               7.4(d, 2H); 7.8(d, 2H); 9.8(s, 1H)                             161.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 45(s, 2H); 4.8(s, 2H);                                7.4(d, 2H); 7.8(d, 2H)                                         162.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 4.5(s, 2H); 5.2(s, 2H);                               7.4(d, 2H); 7.6(d, 2H)                                         163.  CDCl.sub.3                                                                             1.6(t, 3H); 4.5(s, 2H); 5.2(s, 2H); 7.5(d, 2H);                               7.7(d, 2H)                                                     164.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(q, 2H); 4.6(s, 2H); 5.2(s, 2H);                               7.5(bs, 3H); 7.7(d, 2H)                                        165.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(c, 2H); 3.95(s, 2H); 4.65(s, 2H);                             7.45(d, 2H), 7.8(d, 2H)                                        200.  CDCl.sub.3                                                                             1.1(t, 3H); 1.6(m, 1H); 2.2(m, 3H); 2.8(m, 3H);                               4.6(t, 2H); 7.2(m, 2H); 8.1(d, 1H)                             201.  CDCl.sub.3                                                                             2.6(t, 2H); 2.9(t, 2H); 3.5(s, 3H); 7.4(d, 2H);                               7.7(d, 2H)                                                     202.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.9(s, 4H); 4.9(t, 2H);                               6.8(s, 1H); 7.3(m, 2H); 8.0(d, 1H)                             203.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.4-3.4(m, 5H); 3.5(s, 3H);                           7.4(d, 2H); 7.8(d, 2H)                                         204.  CDCl.sub.3                                                                             2.3(s, 3H); 5.4(s, 2H); 5.9(m, 1H); 63(m, 1H);                                7.0(d, 1H); 7.4(d, 2H); 7.6(d, 1H); 7.7(d, 2H)                 205.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.8(t, 2H);                               4.6(s, 2H); 6.9(dd, 2H); 7.5(dd, 4H)                           206.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.4(s, 4H); 2.65(t, 2H);                              2.9(t, 2H); 4.5(s, 2H); 7.2(d, 2H); 7.3(d, 2H)                 207.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(s, 2H); 6.0(s, 2H); 6.9(d, 1H); 7.3(dd, 1H);                              7.5(d, 1H)                                                     208.  CDCl.sub.3                                                                             1.1(t, 3H); 1.5(d, 1H) 2.2(m, 2H); 2.6(t, 2H);                                2.9(t, 2H); 5.7(m, 1H); 7.4(d, 2H); 7.8(d, 2H)                 209.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 3.0(t, 2H);                               4.6(m, 2H); 7.2(m, 2H); 7.4(m, 1H); 7.8(m, 1H)                 210.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.45(s, 3H); 2.6(t, 2H);                              2.9(t, 2H); 4.6(m, 2H); 7.3(m, 4H)                             211.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(m, 2H); 7.4(m, 4H)                                         212.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.5(t, 2H); 2.9(t, 2H);                               3.8(s, 3H); 4.6(m, 2H); 7.0(m, 2H); 7.4(m, 1H);                               7.6(m, 1H)                                                     213.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 3.0(t, 2H);                               4.6(m, 2H); 7.6(m, 2H); 8.0(m, 2H)                             214.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(m, 2H); 7.1(m, 1H); 7.4(m, 1H); 7.6(m, 2H)                 215.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.4(s, 3H); 2.6(t, 2H);                               2.9(t, 2H); 4.6(m, 2H); 7.3(m, 2H); 7.6(m, 2H)                 216.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 3.0(t, 2H);                               4.6(m, 2H); 7.4(m, 2H); 7.7(m, 1H); 7.9(s, 2H)                 217.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(m, 2H); 7.6(t, 1H); 7.7(d, 1H); 8.0(d, 1H);                               8.1(s, 1H)                                                     218.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.7(t, 2H); 3.0(t, 2H);                               4.6(m, 2H); 7.6(t, 1H); 8.3(dd, 2H); 8.7(s, 1H)                219.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               3.8(s, 3H); 4.6(m, 2H); 6.9(m, 1H); 7.4(m, 3H)                 220.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.3(s, 3H); 2.6(t, 2H);                               2.9(t.2H); 3 .9(s, 3H); 4.6(m, 2H); 7.2(s, 2H);                               7.4(s, 1H)                                                     221.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               3.9(s, 3H); 4.6(m, 2H); 6.9(d, 1H); 7.6(dd, 1H);                              7.9(s, 1H)                                                     222.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(m, 2H); 4.6(m, 2H); 7.2(t, 1H); 7.7(m, 1H);                               8.1(dd, 1H)                                                    223.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.0(s, 3H); 4.6(m, 2H); 7.2(d, 1H); 8.0(dd, 1H);                              8.3(d, 1H)                                                     224.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.6(m, 2H); 7.2(q, 1H); 7.5(m, 1H); 7.7(m, 1H)                 225.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.3(s, 3H); 2.6(t, 2H);                               2.9(t, 2H); 4.6(m, 2H); 7.2(m, 1H); 7.5(m, 2H)                 226.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.3(s, 3H); 2.6(t, 2H);                               2.9(t, 2H); 3.9(s, 3H); 4.6(m, 2H); 6.9(d, 1H);                               7.6(m, 2H)                                                     227.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.8(s, 4H);                               2.9(t, 2H); 4.6(m, 2H); 7.3(m, 3H); 7.8(m, 4H)                 228.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 5.0(m, 2H); 7.0-7.5(m,                                10H)                                                           229.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 3.4(t, 2H);                               4.7(m, 2H); 7.5-8.4(m, 6H)                                     230.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.7(t, 2H); 3.4(t, 2H);                               4.7(m, 2H); 7.8(m, 1H); 8.1(m, 2H); 9.7(s, 1H)                 231.  DMSOd6   2.2(s, 3H); 2.4(s, 3H); 2.5(t, 2H); 2.9(t, 2H);                               4.7(s, 2H); 7.6(d, 2H); 7.8(d, 2H)                             232.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 5.0(m, 2H); 7.2(s, 1H);                               7.7(m, 2H); 8.0(m, 4H)                                         233.  DMSOd6   2.6(t, 2H); 2.9(t, 2H); 4.2(s, 2H); 4.3(s, 2H);                               7.5(d, 2H); 7.8(d, 2H); 9.1(bs, 1H)                            234.  CDCl.sub.3                                                                             1.8(s, 3H); 2.0(s, 3H); 2.2-2.4(m, 2H); 2.6(t, 2H);                           3.0(t, 2H); 4.5(bs, 1H); 4.9(q, 2H); 7.3(d, 2H);                              7.8(d, 2H)                                                     235.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.6(t, 2H); 2.9(t, 2H);                               4.7(m, 2H); 7.4(m, 2H); 7.6(s, 1H); 7.9(d, 1H);                               9.0(d, 1H)                                                     236.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 5.0(m, 2H); 7.0(d, 1H);                               7.4(m, 2H); 7.5(d, 1H); 7.7(s, 1H); 7.9(d, 1H);                               8.8(d, 1H)                                                     237.  CDCl.sub.3                                                                             2.3(s, 3H); 2.5(s, 3H); 2.7(t, 2H); 3.0(t, 2H);                               5.4(s, 2H); 6.0(s, 1H); 7.4(d, 2H); 7.7(d, 2H)                 238.  DMSOd6   2.7(t, 2H); 3.0(t, 2H); 5.0(s, 2H); 7.5(d, 2H);                               7.8(d, 2H); 12.4(s, 1H)                                        239.  CDCl.sub.3                                                                             1.1(t, 3H); 2.2(m, 2H); 2.7(t, 2H); 3.0(t, 2H);                               4.4(m, 2H); 5.0(s. 2H); 7.4(d, 2H); 7.8(d, 2H)                 240.  DMSOd6   2.6(m, 2H); 3.0(m, 2H); 4.6(s, 2H); 7.6(m, 6H);                               8.4(s, 1H); 12.2(bs, 1H)                                       241.  CDCl.sub.3                                                                             2.7(t, 2H); 3.0(t, 2H); 4.6(s, 2H); 5.0(s, 2H);                               7.4(d, 2H); 7.8(d, 2H)                                         ______________________________________                                    

EXAMPLES Example 66-(4-chlorophenyl)-2-propargyl-4,5-dihydropyridazinone

a. 6-(4-chlorophenyl)-4,5-dihydropyridazinone

To a mixture of 10 g of 3-(4-chlorobenzoyl)propionic acid and 100 ml ofethanol, 2.4 g of hydrazine monohydrate was added portionwise withstirring and the reaction was refluxed for 2 hours. Upon cooling a whitecrystalline solid was formed which was filtered off and dried to yield9.7 g (99%) of the dihydropyridazinone.

b. 6-(4-chlorophenyl)-2-propargyl-4,5-dihydropyridazinone

A mixture of 0.17 g of sodium hydride (60% in oil) and 50 ml of drydimethylformamide (DMF) was cooled to 5° C. and 0.8 g of thedihydropyridazinone from part a in 25 ml of dry DMF was added dropwise.The reaction was warmed to room temperature for 30 minutes and thencooled to 5° C. Propargyl chloride (0.31 g) was added dropwise and thereaction was stirred overnight at ambient temperature. The reaction wasquenched with 100 ml of water and extracted with ethyl ether (3×100 ml).The organic fractions were combined, washed with water (2×100 ml) andsaturated brine (1×100 ml). The ether extract was then dried overanhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield0.68 g (91%) of compound 6 as a tan solid.

Compounds 7-10, 13, 16, 18, 19, 20, 35, 69, 71, 80, 81, 133, 141,142 and154 were prepared following essentially the same procedure as describedin Example 6b and using the appropriate starting dihydropyridazinone andsubstituting for propargyl chloride the appropriate alkyl halide chosenfrom butyl chloride, crotyl bromide, benzyl bromide, benzoyl chloride,chloromethylcyclopropane, bromoacetonitrile, 2-chloromethylthiophene,bromobutyne, 1,3-dibromo-1-propene, or 1,4-dibromo-2-butyne or amesylate such as 2-butyn-1-yl-methanesulfonate or2-pentyn-1-yl-methanesulfonate.

Compound 52 was isolated by chromatography (silica gel, 30:70 ethylacetate/hexane) from an alkylation with propargyl chloride.

Compound 75 was isolated as an impurity from the preparation of compound71.

Example 11 6-(4-methoxyphenyl)-2-(2'-butynyl)-4,5-dihydropyridazinone

a. 2-butyn-1-yl-methanesulfonate

To a solution of 25 g of 2-butyn-1-ol in 200 ml of anhydrous diethylether, 72 g of triethylamine was added in one portion and the reactionmixture was cooled to 0° C. Methanesulfonyl chloride (40.8 g) was addeddropwise maintaining the temperature below 5° C. Then the reaction wasstirred for 2 hours at 0°-5° C. and the triethylamine salts werefiltered off and washed with 100 ml of ether. The ether fractions werecombined, washed with water (100 ml), brine (100 ml), dried overmagnesium sulfate and evaporated in vacuo to yield 39.6 g of themesylate as a yellow liquid.

b. 6-(4-methoxyphenyl)-2-(2'-butynyl)-4,5-dihydropyridazinone

The starting 6-(4-methoxyphenyl)-4,5-dihydropyridazinone was preparedfollowing essentially the procedure described in Example 6a andalkylated with the mesylate from 11a following essentially the proceduredescribed in 6b.

Compounds 17, 21, 22, 24, 25, 29, 84, 85, 107, 132 and 137 were preparedfollowing essentially the same procedure, using the appropriatesubstituted dihydropyridazinone and preparing the appropriate mesylateusing the appropriate alcohol chosen from 3-phenyl-2-propyn-1-ol,3-pentyn-1-ol, 2-hexyn-1-ol, 3-methyl-2-butyn-1-ol,3-t-butylpropyn-1-ol, 2-penten-4-yne-1-ol, 2-decyn-1-ol, or2-butyn-1-ol.

Compound 138 was isolated from the reaction mixture during thepreparation of Compound 137.

Example 12 6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. ethyl 3-bis(di-t-butylcarboxy)propionate

To a solution of 12.5g (0.11 mole) of potassium t-butoxide in 120 ml oft-butanol was added 20 g of di-t-butylmalonate dropwise at roomtemperature. A solid paste was formed that made stirring difficult.After 15 minutes at room temperature 16.7 g of ethyl bromoacetate wasadded dropwise and the resulting mixture stirred at room temperatureovernight. The alcohol was removed in vacuo, the residue was taken up in150 ml of water and the resulting mixture extracted with ether (3×80ml). The combined ether layers were dried (magnesium sulfate, (MgSO₄))and evaporated. The residue was distilled through a short Vigreuxcolumn. The fractions boiling at 125°-135° C./1 mm were collected toyield 14.2 g (51%) of the triester as a clear oil.

b. ethyl 3-(4-chlorophenyl)-bis(di-t-butylcarboxy)propionate

Sodium hydride (60% in mineral oil, 240 mg, 5 mmoles) was suspended indry dimethylformamide (DMF) (20 ml) and cooled to 0° C. To the resultingmixture was added ethyl 3-bis(di-t-butylcarboxy)propionate (1.51g, 5mmoles) dropwise. After 10 minutes at 0° C. 4-chlorobenzoyl chloride(0.88g, 5 mmoles) was added dropwise and the resulting suspension wasstirred at 0° C. during 1/2 hour. The reaction mixture was poured intosaturated aqueous ammonium chloride (100 ml) and extracted with ether(3×80 ml), the combined organic layers were washed with brine (3×100ml), dried and evaporated to yield ethyl3-(4-chlorophenyl)-3-bis(di-t-butylcarboxy)propionate.

c. 3-(4-chlorobenzoyl)propionic acid

The compound obtained in part b was dissolved in 50 ml of toluene and100 mg of p-toluenesulfonic acid was added and the resulting solutionwas heated 80°-85° C. overnight. After cooling at room temperature, thereaction mixture was extracted with 2% aqueous sodium bicarbonate, driedand evaporated to yield 3-(4-chlorobenzoyl)propionic acid.

d. 6-(4-chloropheny)-4,5-dihydropyridazinone

To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absoluteethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solidwas formed which dissolved after heating. The resulting solution wasrefluxed for 3 h, cooled and the solid formed filtered and dried toyield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone.

e. 6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

Method i

To a suspension of sodium hydride (NaH) (210 mg 60% in mineral oil) indry DMF at 0° C. was added 6-(4-chlorophenyl)-4,5-dihydropyridazinone(1.0 g) in DMF (30 ml) dropwise. The yellow mixture was stirred at 0° C.until gas evolution ceased. To the mixture was added 1-bromopent-2-yne(0.8 g) at 0° C. and kept at that temperature for 1/2 h. The reactionmixture was poured into saturated aqueous ammonium chloride (100 ml) andextracted with ether (3×100 ml). The combined organic layers were washedwith brine (2×50 ml), dried and evaporated. Trituration of the oilyresidue with hexane yielded the product as a light yellow solid.

Method ii

To a stirred mixture of 1-bromopent-2-yne (1.4 g),6-(4-chlorophenyl)-4,5-dihydropyridazinone (1.0 g), toluene (150 ml) andtetrabutylammonium hydrogen sulfate (100 mg) was added 50% aqueous NaOH(1.9 g) added dropwise. The reaction mixture was heated with continuousstirring at 50° C. for 4 h. The reaction mixture was cooled to roomtemperature and the layers separated. The organic layer was washedseveral times with water, dried and evaporated to yield 1.2 g (91%) of6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone as a whitesolid.

Using the same procedure as described for this example compounds 32, 40,41, 42, 57-66, 73, 78, 79, 82, 90, 91, 96-99, 103, 104, 144, 147 and 148were made starting from the appropriate benzoyl chloride and alkylatingwith the appropriate alkyl halide or mesylate.

Example 15 6-(4-chlorophenyl)-4,5-dihydro-2-t-butylpyridazinone

To a solution of 4-chlorobenzoylpropionic acid (4.24 g) in n-butanol(150 ml) was added anhydrous sodium acetate (1.54 g) andt-butylhydrazine hydrochloride (2.75 g) portionwise at room temperature.The resulting mixture was refluxed for 9 hours distilling off 65 ml ofn-butanol during that time. The resulting mixture was cooled and pouredinto water (500 ml) and extracted with methylene chloride (3×150 ml).The combined organic layers were washed with 2% aqueous sodium hydroxide(3×100 ml), water (2×100 ml), 2% aqueous hydrochloric acid (3×100 ml),and water (1×100 ml), dried and evaporated under vacuum yielding 1.71 gof the expected product.

Compound 14 was prepared using essentially the same procedure and usingphenylhydrazine hydrochloride in place of t-butylhydrazinehydrochloride.

Example 266-(4-chlorophenyl)-5-methyl-2-(2'-butynyl)-4,5-dihydropyridazinone

a. 2-methyl-3-(4-chlorobenzoyl)propionic acid

To a mixture of 11.4 g of methyl succinic anhydride and 38.7 g ofchlorobenzene, 30 g of aluminum chloride was added below 35° C. Then thereaction mixture was warmed to 60°-70° C. for 2 hours, cooled andcautiously poured onto 500 g of ice. The mixture was extracted withether (4×100 ml). The organic layers were combined, washed with water(2×100 ml) and brine (2×100 ml), then dried over magnesium sulfate andevaporated in vacuo to yield a viscous oil which crystallized onstanding. The solid was filtered off to yield 12.1 g of1-methyl-3-(4-chlorobenzoyl)propionic acid. The remainder of thenoncrystalline material was identified as2-methyl-3-(4-chlorobenzoyl)propionic acid.

b. 6-(4-chlorophenyl)-5-methyl-2-(2'-butynyl)-4,5-dihydropyridazinone

The 1-methyl-3-(4-chlorobenzoyl)propionic acid from part a was reactedessentially as described in Example 6 to yield Compound 26.

Compound 27 was prepared following essentially the same procedure andusing the 2-methyl-3-(4-chlorobenzoyl)propionic acid from part a above.

Compound 106 was prepared following essentially the same procedure andusing perfluorosuccinic anhydride in place of methyl succinic anhydridein part a.

Example 286-(3,4-dichlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3,4-dichlorobenzoylpropionic acid

To a mixture of 1,2-dichlorobenzene (29.4 g) and succinic anhydride (10g) was added anhydrous aluminum chloride (28.0 g) portionwise withstirring at room temperature. The resulting mixture was heated at 80° C.for 6 hours, cooled to room temperature and poured into ice-water (600g). The aqueous suspension was extracted with ethyl ether (4×150 ml),the combined organic layers were washed with water (2×150 ml), dried andevaporated. The oily-solid residue was triturated with hexane-ether(8:2) yielding the product as a yellow solid.

b. 6-(3,4-dichlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The 3,4-dichlorobenzoylpropionic acid was converted to the desiredproduct using essentially the same procedures as described in Example12d,e.

Compounds 23, 135 and 136 were made from the appropriate startingmaterials using essentially the same procedure.

Example 306-(4-chlorophenyl-2-(2'-pentynyl)-4-phenyl-4,5-dihydropyridazinone

To a mixture of the 3-(4-chlorobenzoyl)-2-phenylpropionitrile (0.037moles) in 100 ml absolute ethanol there was cautiously added 10 ml ofconc H₂ SO₄ and the mixture was refluxed overnight. The ethanol wasremoved in vacuo and the residue was dissolved in 200 ml ethyl ether.The ether solution was washed with H₂ O (2×100 ml) and brine (100 ml),then dried over anhydrous MgSO₄ and stripped to yield 9.2 gms (79%) of ayellow oil. The keto ester was reacted as described in Example 11b-e(i)to obtain the desired compound.

Example 33 6-(4-phenoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 1-bromo-2-butyne

The mesylate of 2-butyn-1-ol was prepared as described in Example 11a.To a solution of 27 g of the mesylate in 200 ml of dry tetrahydrofuranwas added 70 g of anhydrous lithium bromide portionwise at roomtemperature. The mixture was stirred overnight at room temperature, thenpoured into 250 ml of dry ether and washed with water (2×100 ml) andbrine (2×100 ml). The ether extract was dried over anhydrous magnesiumsulfate and stripped to yield 21 g of 1-bromo-2-butyne as a yellowliquid.

b. 6-(4-phenoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The phenoxydihydropyridazinone was prepared from the correspondingketoacid and alkylated as described in example 6 to yield 0.7 g ofcompound 33 as a tan solid.

Example 346-(4-chlorophenyl)-2-(3'-methyl-2'-butynyl)-4,5-dihydropyridazinone

a. 3-methyl-2-butyn-1-ol

A solution of 3-methyl-1-butyne in 200 ml of dry THF was cooled to -78°C. and n-butyl lithium (0.160 mole) was added dropwise below 60° C.After stirring for 1 hour at -78° C., gaseous formaldehyde wasintroduced into the reaction by heating paraformaldehyde (7 g) to a meltand applying a positive pressure to the system to create a formaldehydeatmosphere. The reaction mixture was stirred for 1 hour and then allowedto warm to room temperature and quenched with 100 ml saturated ammoniumchloride solution and extracted with ether (3×100 ml). The organiclayers were combined, washed with brine (3×100 ml), dried over magnesiumsulfate and evaporated in vacuo to yield 3-methyl-2-butyn-1-ol in 60%yield.

b. 6-(4-chlorophenyl)-2-(3'-methyl-2'-butynyl)-4,5-dihydropyridazinone

The alcohol was mesylated using essentially the procedure described inExample 11a and alkylated using essentially the procedure described inExample 6b to yield 1.1 g of Compound 34.

Compounds 45 and 46 were prepared following essentially the sameprocedure using isopropyl acetylene or 3,3-dimethyl-1-butyne in place of2-methyl-1-butyne in part a.

Compound 50 was prepared following essentially the same procedure andpreparing 1-chloro-5-hydroxy-2-pentyne from propargyl chloride andethylene oxide.

Example 366-(4-chlorophenyl)-2-(2'-thienylmethyl)-4,5-dihydropyridazinone

a. 2-chloromethylthiophene

A solution of 10 g of 2-thiophenemethanol, 9.3 g of triethylamine and250 ml of ether was cooled to 5° C. and 11 g of thionyl chloride wasadded dropwise. The reaction mixture was stirred at 5°-0° C. for 30minutes and then warmed to room temperature. The precipitated solid wasfiltered off and the ether solution was washed with 100 ml of 0.1Mhydrochloric add and then 100 ml of brine. The ether extract was driedover magnesium sulfate and evaporated in vacuo to yield the desiredchloride in 75% yield.

b. 6-(4-chlorophenyl)-2-(2'-thienylmethyl)-4,5-dihydropyridazinone

Following essentially the procedure describe in Example 6b, the chloridewas used to alkylate 6-4-chlorophenyl)-4,5-dihydropyridazinone to yieldcompound 36.

Example 37 6-(3-chlorophenyl)-2-(2'-butynyl)-4,5-dihydropyridazinone

a. 3-(3-chlorobenzoyl)propionic acid

Sodium (11 g, spheres) was added to 200 ml ethanol with stirring. Whenthe gas evolution ceased, methyl 3-chlorobenzoate (10 g, 0.057 mole) anddimethyl succinate (9.0 g, 0.615 mole) were added rapidly and themixture was stirred for 5 minutes at room temperature. The mixture wasslowly concentrated on a rotary evaporator to yield a greenish pastewhich was slurried in 100 ml ether and an additional 2 ml of dimethylsuccinate was added. The reaction was evaporated to a paste, quenchedwith water and extracted with ether. The ether extracts were washed withwater and brine, dried and evaporated in vacuo.

The starting material was distilled from the residue and the remainingmaterial was refluxed in 6N hydrochloric add for 2 days to yield 1.6 gof the desired ketoacid which was filtered off.

b. 6-(3-chlorophenyl)-2-(2'-butynyl)-4,5-dihydropyridazinone

The ketoacid from part a was reacted essentially as described in Example6a and b to yield 0.75 g of compound 37 as a tan solid.

Compounds 38 and 140 were prepared using essentially the same procedureusing ethyl 3,5-dichlorobenzoate or ethyl 2-thiophenecarboxylate inplace of methyl 3-chlorobenzoate.

Example 396-(4-chloro-3-nitrophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 4-chloro-3-nitrobenzoylpropionic acid

To fuming nitric acid (150 ml) was added p-chlorobenzoylpropionic acid(20.0 g), slowly portionwise at 0° C. After the addition was completedthe resulting mixture was stirred at 0° C. for 30 minutes and theresulting white solid was suction filtered and washed with water untilthe pH of the washing liquids was neutral, then dried to yield3-(4-chloro-3-nitrobenzoyl)propionic acid as a white solid (13.0 g).

b. 6-(4-chloro-3-nitrophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The 4-chloro-3-nitrobenzoylpropionic acid from step a was converted tothe final product using essentially the procedure of Example 6a-b.

Example 446-(3,5-dichloro-4-methylphenyl-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3-(3,5-dichloro-4-methylbenzoyl)propionic acid

To a mixture of 3-(4-methylbenzoyl)propionic acid (7.5 g) and methylenechloride (250 ml) was added slowly portionwise aluminum chloride (15 g)at 0° C. After the addition was completed chlorine gas was bubbled inslowly at 0° C. After 6 hours the reaction mixture was poured into amixture of hydrochloric acid and ice and extracted with methylenechloride (3×150 ml), the combined organic layers were washed with water,dried and evaporated under vacuum yielding3-(3,5-dichloro-4-methylbenzoyl)propionic acid as a yellow solid (4.5g).

b.6-(3,5-dichlorophenyl-4-methylphenyl-2-(2'-pentynyl)-4,5-dihydropyridazinone

The 3-(3,5-dichloro-4-methylbenzoyl)propionic acid from step a wasconverted to the final product using essentially the procedures ofExample 6a-b.

Compound 43 was prepared following essentially the same procedure.

Example 476-(4-chlorophenyl)-2-(4'hydroxy-2'-pentynyl)-4,5-dihydropyridazinone

a. 2-hydroxy-5-iodo-3-pentyne

Propargyl chloride was hydroxyethylated with acetaldehyde and n-butyllithium as described in Example 34a.

A solution of 2-hydroxy-5-chloro-3-pentyne (2.0 g) and anhydrous sodiumiodide (12.6 g) in 100 ml of dry acetone was stirred overnight at roomtemperature. The acetone was evaporated in vacuo and the residue wasextracted with ether (2×100 ml). The ether extracts were washed withwater (2×100 ml) and brine (100 ml), dried and evaporated in vacuo toyield the iodide as a red liquid.

b. 6-(4-chlorophenyl)-2-(4'hydroxy-2'-pentynyl)-4,5-dihydropyridazinone

The iodide was used essentially as described in Example 6b, except that2 equivalents of sodium hydride were used and the reaction mixture wasacidified to pH 5 before extraction to obtain the desired product.

Example 486-(4-chlorophenyl)-2-(4'methoxy-2'-pentynyl)-4,5-dihydropyridazinone

To a solution of 100 milligrams of compound 47 and 20 ml of drymethanol, 4 ml of thionyl chloride was added dropwise over 25 minutes.Upon completion of the addition, the methanol solution was evaporated todryness and the residue was dissolved in 100 ml of ether, washed with100 ml of water, 100 ml of brine, dried over magnesium sulfate andevaporated in vacuo to yield 100 milligrams of compound 48 as a yellowoil.

Compound 55 was prepared from compound 54 following essentially the sameprocedure.

Example 496-(4-chlorophenyl)-2-(4'acetoxy-2'-pentynyl)-4,5-dihydropyridazinone

To a solution of 100 milligrams of compound 47 in 50 ml of methylenechloride there was added 54 miligrams of pyridine and 69 milligrams ofacetic anhydride. The reaction mixture was stirred overnight andevaporated to dryness. The residue was dissolved in 200 ml of ether,washed with 100 ml of water, 100 ml of brine, dried over magnesiumsulfate and evaporated to yield 100 milligrams of compound 49 as acolorless oil.

Example 516-(4-chlorophenyl)-2-(5'-fluoro-2'-pentynyl)-4,5-dihydropyridazinone

A solution of 120 milligrams of compound 50 and 50 ml of methylenechloride was cooled to 0° C. and a solution of 130 mg ofdiethylaminosulfur trifluoride (DAST) in 15 ml of methylene chloride wasadded dropwise. The reaction mixture was stirred at 0°-5° C. for 1 hourand overnight at room temperature, then quenched with 100 ml of brineand extracted with methylene chloride (2×100 ml). The combined organicextracts were washed with brine (100 ml) and evaporated to yield ayellowish oil which was chromatographed on 50 g of silica (50/50 ethylacetate/hexane) to yield 60 milligrams of compound 51.

Following essentially the same procedure, compounds 53 and 89 wereprepared starting from compounds 47 and 88.

Example 546-(4-chlorophenyl)-2-(3'-carboxy-2'-propynyl)-4,5-dihydropyridazinone

a. 3-carboxypropargyl chloride

A solution of 10 g of propargyl chloride in 200 ml of dry ether wascooled to -70° C. and 100 ml of methyllithium (1.4 molar solution inhexane) was added dropwise in 30 minutes. The reaction mixture wasstirred under a carbon dioxide atmosphere for 45 minutes at -60° C.,then slowly warmed to room temperature, quenched with 100 ml of brine,acidified to pH 5 and extracted with ether (3×100 ml). The ether layerswere combined, washed with 100 ml of water, 100 ml of brine, dried overmagnesium sulfate and evaporated to yield a dark brown liquid which wasfractionally distilled (0.4 mm Hg, 187°-190° C.) to yield 2.6 g of theacid.

b. 6-(4-chlorophenyl)-2-(3'-carboxy-2'-propynyl)-4,5-dihydropyridazinone

The acid from part a was used following essentially the proceduredescribed for compound 47 to obtain compound 54 as a tan solid.

Example 566-(4-chlorophenyl)-2-(3'-vinyl-2'-propynyl)-4,5-dihydropyridazinone

A solution of 1.0 g of compound 6, 0.62 g of vinyl iodide and 100 ml oftriethylamine was degassed with nitrogen and 50 milligrams each ofcopper(I)iodide and bis-triphenylphosphine palladium dichloride wasadded. After stirring overnight at 50° C., the triethylamine wasevaporated and the residue was redissolved in 150 ml of ether, passedthrough 10 g of silica and evaporated to yield 1.0 g of compound 56 as ayellow oil.

Compound 67, 68, 78, 119, were prepared following essentially the sameprocedure using the appropriate starting material and substituting2-iodothiophene, 1-chloro-4-iodobenzene or iodofluoroethylene in placeof vinyl iodide when appropriate.

Compound 70 was prepared from compound 69 and 3-methylbutyne followingessentially the same procedure.

Example 726-(4-chlorophenyl)-2-(4'-chloro-2'-butynyl)-4,5-dihydropyridazinone

To a solution of 2.5 g of 6-(4-chlorophenyl)-4,5-dihydropyridazinone in100 ml of toluene there was added 100 milligrams of tetrabutylammoniumhydrogen sulfate and with rapid stirring added 4.7 g of 50% aqueoussodium hydroxide. Then 1,4-dichloro-2-butyne (7.4 g) in 50 ml of toluenewas added dropwise and the reaction mixture was heated to 50°-60° C. for4 hours. The reaction mixture was cooled and poured into 200 ml ofwater. The organic phase was separated and the aqueous phase wasextracted with ether (2×100 ml). The combined organic phases were washedwith 100 ml of water, 100 ml of brine and dried over magnesium sulfateand evaporated to yield a crude product which was chromatographed toyield 1.9 g of compound 72.

Compound 128 was prepared following essentially the same procedurestarting with 6-(4-chloro-3-fluorophenyl)pyridazinone and using powderedpotassium hydroxide instead of sodium hydroxide.

Compound 100 was prepared following essentially the same procedure andusing the mesylate prepared from 1-bromo-2-pentyn-4-ene described inexample 33.

Example 746-(4-chloro-3-fluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

Method A

a. 4-chloro-3-fluorobenzoic acid

Method i

0.7 Gram-atom (17.0 g) of magnesium turnings was covered with 100 ml ofdry ethyl ether and 0.05 mole (0.95g) of 1,2-dibromoethane was addeddown the side of the flask in such a way that it did not mix with theether but contacted the magnesium. The mixture was allowed to standwithout stirring until bubbles formed around the turnings and the etherbecame cloudy. Then the mixture was stirred and warmed to mild refluxand 0.62 mole (130.0 g) of 4-chloro-3-fluorobromobenzene in 500 ml ofdry ether was added to the flask at such a rate that there was a mildreflux. The refluxing and stirring were continued for 30 minutes afterthe addition of the halide was completed.

The reaction mixture was then cooled to -10° C. and dry CO₂ was bubbledin below -2° C. The reaction was complete when the temperature fellbelow -10° C. and did not rise when increasing the rate of flow of CO₂.To the cold mixture was added 150 ml of 7.5% HCl at 0° C. The layerswere separated and the aqueous layer was washed with ether (3×150 ml).The combined organic layers were washed with water (2×200 ml), dried andevaporated to yield the product as a white solid. 98 g (91% yield).

Method ii

A mixture-of 110 g of 98% H₂ SO₄ and 192 g (0.97 mole) of4-chloro-3-fluorobenzotrifluoride was stirred and then heated cautiouslyuntil the hydrogen fluoride evolution started (approx. 130° C.). Thereaction mixture was heated at 130°-135° C. for 17 hours, and pouredinto 1 Kg of ice. The resulting white precipitate was filtered off andwashed with water until the pH of the washing liquids was neutral, andthe precipitate was dried to yield 165 g (98%) of the expected add as awhite solid.

b. 6-(4-chloro-3-fluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The 4-chloro-3-fluorobenzoic add was then converted to the correspondingadd chloride by standard means. The desired product was producedfollowing essentially the procedures of Example 11b-e.

Method B

a. 4-chloro-3-fluorobenzoyIpropionic acid

To a solution of succinic anhydride (6.0 g) in tetrahydrofuran (60 ml)was added dropwise the Grignard prepared from 1.5 g (0.062 mole) ofmagnesium turnings and 10.5 g (0.05 mole) of1-bromo-4-chloro-3-fluorobenzene using the procedure of part a. When theaddition was completed, the resulting suspension was stirred for 2 hoursat 45° C. after which water (100 ml) was added slowly and the resultingmixture was acidified with concentrated hydrochloric acid to pH=1. Theether layer was separated and extracted with 5% aqueous sodium hydroxide(3×100 ml). The combined aqueous solutions were washed with ether (1×100ml). The combined basic aqueous layers were acidified with concentratedhydrochloric acid to pH 1 and extracted with ethyl acetate (3×150 ml).The combined organic extracts were washed with water (1×150 ml) andbrine (1×150 ml), dried over anhydrous magnesium sulfate and evaporatedin vacuo to give 7.1 g (62%) of the product as a yellow orange solid.

The resulting acid was converted to the desired product using theprocedure of Example 11d-e.

Compound 83 was prepared following essentially the same procedure.

Example 766-(4-chlorophenyl)-2-(4'-fluoro-2'-butynyl)-4,5-dihydropyridazinone

a. 4-tetrahydropyranoxy-2-butyn-1-ol

To a mixture of 5.0 g of 2-butyne-1,4-diol and 10 milligrams ofp-toluenesulfonic add and 150 ml of dry ether there was added dropwisewith stirring at room temperature 4.9 g of 3,4-dihydro-2H-pyran. Afterstirring overnight at ambient temperature the ether was evaporated andthe residue was poured into 200 ml of water. The aqueous solution wasextracted with hexane (2×100 ml) and then re-extracted with ether (3×100ml). The combined ether extracts were washed with 100 ml of brine, driedover magnesium sulfate and evaporated to yield 6.8 g of4-tetrahydropyranoxy-2-butyn-1-ol.

b. 6-(4-chlorophenyl)-2-(4'-hydroxy-2'-butynyl)-4,5-dihydropyridazinone

The alcohol was converted to the mesylate using essentially theprocedure described in Example 11a and the mesylate was used in thealkylation following essentially the procedure describe in Example 6b.The resulting compound was dissolved in 100 ml of methanol. AmberliteIR20® (2 g) resin was washed with 10 ml of methanol and added to thereaction mixture. After stirring for 1 hour, the resin was filtered offand the methanol was evaporated. The oily residue was triturated withhexane to yield 1.3 g of the desired alcohol as a tan solid.

c. 6-(4-chlorophenyl)-2-(4'-fluoro-2'-butynyl)-4,5-dihydropyridazinone

The alcohol from part b was treated with DAST following essentially theprocedure described in Example 51. Silica gel chromatography (50:50hexane/ethyl acetate) of the crude product yielded 300 milligrams ofcompound 76 as a pale yellow solid.

Example 77 6-(4-chlorophenyl)-2-epoxymethyl-4,5-dihydropyridazinone

To a mixture of 1.0 g of compound 56 and 50 ml of methylene chloride,1.3 g of m-chloroperbenzoic acid was added portionwise at roomtemperature. The reaction mixture was stirred overnight at ambienttemperature then poured into 100 ml of methylene chloride and washedwith saturated sodium bisulfite (2×100 ml), brine (100 ml), dried overmagnesium sulfate and evaporated to yield a residue which waschromatographed on silica (50:50 ethyl acetate/hexane) to yield 350milligrams of Compound 77 as a white solid.

Example 866-(4-chlorophenyl)-2-(4'-trimethylsilyl-2'-butynyl)-4,5-dihydropyridazinone

The bromide of trimethylsilyl propargyl alcohol was prepared followingessentially the procedures described in Examples 11a and 33a. To amixture of 300 ml of dry tetrahydrofuran and 4.8 g of sodium hydride(60% in oil) there was added 25 g of6-(4-chlorophenyl)-4,5-dihydropyridazinone dissolved in 200 ml oftetrahydrofuran. When the hydrogen gas evolution stopped, the solventwas removed in vacuo. The resulting solid was slurried in hexane andfiltered off to yield 27.4 g of the sodium salt as a whitenon-hydroscopic solid.

A solution of 1.0 g of the sodium salt in 50 ml of dimethylformamide wascooled to 5° C. and 0.9 g of 1-bromo-3-trimethylsilyl-2-propyne wasadded dropwise. After stirring for 30 minutes at 5° C., the reactionmixture was warmed to room temperature, quenched with 100 ml of waterand extracted with ether (3×100 ml). The ether extracts were combined,washed with 100 ml of water, 100 ml of brine, dried over magnesiumsulfate and evaporated to yield the crude product which waschromatographed on silica gel (30:70 ethyl acetate/hexane) to yield 0.5g of compound 86 as a white solid.

Compounds 96 and 124 were prepared using essentially the same alkylationprocedure and the mesylate of 2-octyn-1-ol or 2,4-pentadiyn-1-ol(example 93).

Compound 105 was prepared following essentially the same procedure toform the sodium salt of 6-(4-chlorophenyl)pyridazinone which wasalkylated with 3-chlorobenzyl bromide.

Compound 101 was prepared following essentially the same procedure andusing the mesylate of 2-hexyn-4-ene-1-ol prepared following essentiallythe procedure described in example 56 starting from propargyl alcoholand 1-bromo-1-propene.

Compounds 102 and 103 were obtained from compound 101 by chromatographyon an HPLC semiprep silica column eluting with 1:3 ethylacetate/heptane.

Example 876-(4-chlorophenyl)-2-(4'-aldehydo-2'-butynyl)-4,5-dihydropyridazinone,diethyl acetal

a. 4-hydroxy-2-butynylaldehyde diethylacetal

To a mixture of magnesium turnings (18.5 g) and 350 ml drytetrahydrofuran, bromoethane (83 g) was added dropwise below 50° C.After all the magnesium had reacted, a solution of propargyl alcohol (20g, 0.356 mole) in 100 ml of tetrahydrofuran was added dropwise. Themixture was refluxed for one hour and ethyl orthoformate (53 g, 0.356mole) in 50 ml tetrahydrofuran was added dropwise, as rapidly aspossible. The mixture was refluxed for 8 hours and stirred overnight atroom temperature. The mixture was cautiously poured into 500 ml ice cold20% aqueous ammonium acetate and extracted with 3×100 ml ethyl ether.The ether extract was washed with H₂ O (2×100 ml) and 100 ml brine,dried over anhydrous MgSO₄ and stripped to yield 42 g of the crudeproduct which was distilled at 115°-120° C. (3 mm Hg) and 31 g pureproduct (56% yield) was isolated.

b. 6-(4-chlorophenyl)-2-(4-aldehydo-2'-butynyl)-4,5-dihydropyridazinone,diethyl acetal

The hydroxy compound was converted to the corresponding mesylate thenused to alkylate 6-(4-chlorophenyl)-4,5,-dihydropyridazinone asdescribed in Examples 11a and 6b(i), respectively.

Example 886-(4-chlorophenyl)-2-(4-aldehydo-2'-butynyl)-4,5-dihydropyridazinone

A mixture of the diethylacetal (Compound 86) (4.0 g), formic acid (10ml), and water (20 ml) was heated to 40° C. with stirring for threehours. The mixture was poured into 100 ml H₂ O and extracted with 3×100ml ethyl ether and washed with 100 ml sodium bicarbonate (saturated) and100 ml brine. The ether extract was dried over anhydrous MgSO₄ andstripped to yield 2.2 g of a tan solid characterized to be the aldehyde(80% yield).

Example 936-(4-chlorophenyl)-2-(2',4'-pentadiynyl)-4,5-dihydrdropyridazinone

a. 2,4-pentadiyn-1-ol

To a suspension of sodamide (prepared from 20.5 g (0.89 gram atoms) ofsodium and 500 ml liquid ammonia) was added dropwise at -40° C.1,4-dichloro-2-butyne (37 g, 0.3 mole). After stirring at -40° C. for 30minutes, a suspension of dry paraformaldehyde (9 g) was addedportionwise in 100 ml anhydrous diethyl ether (Et₂ O). After stirringfor 1 hour at -40° C., ammonium chloride (40 g, 0.75 moles) was addedportionwise as a solid followed by 200 ml of Et₂ O. The ammonia wasallowed to evaporate overnight and the solution was filtered throughCelite®. The solids were washed with Et₂ O (100 ml) and the ether layerwas washed with saturated brine. The ether layer was dried overanhydrous MgSO₄ and stripped to yield 16 g of 2,4-pentadiyn-1-ol as ared oil (67% yield).

b. 6-(4-chlorophenyl)-2-(2',4'-pentadiynyl)-4,5-dihydropyridazinone

The alcohol was converted to the mesylate following essentially theprocedure described in Example 11a. The mesylate was used in thealkylation as described in Example 86 to yield the expected product.

Compound 125 was prepared following essentially the same procedure andusing the appropriate pyridazinone.

Example 94 6-(4-chlorophenyl)-2-(3'-cyclohexyl-2'-propenyl)pyridazinone

a. 3-cyclohexyl-2-propyn-1-ol

To a solution of ethyl magesium bromide (prepared from 2.5 g ofmagnesium turning and 11.3 g of bromoethane) in ether was added dropwisea solution of 10.2 g of cyclohexylacetylene in ether and the reactionmixture was refluxed for 2 hours. The reaction mixture was cooled toambient temperature and anhydrous formaldehyde (prepared from thethermal decomposition of 50 g of paraformaldehyde for 20 minutes) wasbubbled into the mixture. After cooling, the reaction was quenched withsaturated ammonium chloride and extracted with ether (2×100 ml). Thecombined ether extracts were washed with brine, dried over magnesiumsulfate and evaporated to yield the product which was distilled underhigh vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.

b. 6-(4-chlorophenyl)-2-(3'-cyclohexyl-2'-propenyl)pyridazinone

Using the alcohol from part a and following essentially the proceduresdescribed in Examples 11 and 86, compound 94 was prepared.

Compound 95 was prepared following essentially the same procedurestarting with 1-cyclohexyl-2-propyne.

Example 109 6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinone

a. 6-(4-chlorophenyl)pyridazinone

To a solution of 6-(4-chlorophenyl)-4,5-dihydropyridazinone (11.75 g)and glacial acetic acid (100 ml) was added dropwise 3 ml of bromine andthe mixture was heated at 60°-70° C. for 3 h. The resulting mixture wascooled and slowly poured into 400 ml of cold water. The resulting whitesolid was filtered and dried to yield 10.83 g (89%) of6-(4-chlorophenyl)pyridazinone.

b. 6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinone

The pyridazinone obtained in part a above was alkylated as described inExample 6 to obtain 6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinone.

Compounds 108, 110-118, 120, 121, 127 and 129-131 were preparedfollowing essentially the same procedure starting with the appropriatedihydropyridazinone and alkylating agent.

Example 122 6-(4-chlorophenyl)-4,5-difluoro-2-(2'-pentynyl)pyridazinone

a. 1,4-dichloro-1,2,2-trifluorocyclobut-3-ene

To a solution of 1,1,2 trichloro-2,3,3-trifluorocyclobutane (55.5 g) in100 ml of anhydrous ether, triethylamine (40 ml) was added dropwise over30 min at room temperature, and the mixture was stirred overnight atambient temperature. The mixture was then stirred with 120 ml H₂ O and7.5 ml of concentrated HCl. The ether layer was washed with H₂ O (100ml), brine (100 ml), dried over anhydrous MgSO₄, and evaporated invacuo. The residue was distilled fractionally atmospheric pressure from64°-68° C. to yield 36 g (79%) of a colorless liquid as pure product.

b. 2-chloro-2,3,3-trifluorosuccinic acid

To potassium hydroxide (11.3 g) in 250 ml H₂ O, potassium permanganate(56 g) was added in one portion and the mixture was stirred untileverything was in solution. Then1,4-dichloro-1,2,2-trifluorocylobutene-3-ene (31.1 g) was added dropwiseat 15°-20° C. over 30 minutes. The mixture was stirred for 12 hours atroom temperature, filtered through Celite® and washed with water. Theaqueous solution was acidified with 23 ml concentrated H₂ SO₄ (4×100ml). The acid solution was extracted with ether and dried over anhydrousMgSO₄. The ether layer was stripped to yield the product as 26 g (71%)of a colorless liquid.

c. 2,2,3-trifluorosuccinic acid

To a stirring solution of the chlorotrifluorosuccinic acid (part b)(24.5 g) in 200 ml dioxane was added portionwise zinc metal (85 g) andthe mixture was stirred at ambient temperature for 10 hours to yield aviscous liquid which was decanted from the unreacted zinc. Most of thedioxane was evaporated in vacuo. The residue was dissolved in 100 ml H₂O and a solution of 7.7 ml of concentrated H₂ SO₄ in 25 ml of water wasadded. The solution was extracted with ether (3×100 ml) and dried overanhydrous MgSO₄. The organic layer was stripped to yield 8.3 g (32%) ofthe product as a crystalline solid.

d. 2,2,3-trifluorosuccinic anhydride

A slurry of the succinic acid (part c) (8.0 g) and phosphorus pentoxide(14.7 g) was heated and the anhydride was distilled through a 6" Vigreuxcolumn at 15 mm Hg. The colorless liquid was collected at 60°-68° C. Theproduct was isolated in 53% yield (3.0 g).

e. 6-(4-chlorophenyl)-4,5-difluoro-2-(2'-pentynyl)-pyridazinone

The anhydride was reacted with chlorobenzene as described in Example 26ato produce a mixture of fluorinated ketoacids. Cyclization withhydrazine yielded a single difluorodihydropyridazinone. Alkylation with1-bromo-2-pentyne yielded6-(4-chlorophenyl)-4,5-difluoro-2-(2'-pentynyl)-pyridazinone.

Example 1246-(4-chlorophenyl)-2-(3'-tri-n-butyltin-2'-propynyl)-4,5-dihydropyridazinon

A solution of 6.0 g of compound 118 in 50 ml of dry tetrahydrofuran wascooled to -78° C. and 17.4 ml of 1.6M n-butyllithium in hexane was addeddropwise. The solution was stirred at -78° C. for 30 minutes and then asolution of 8.0 g of tributyltin chloride in 30 ml of drytetrahydrofuran was added dropwise. The reaction mixture was allowed towarm to room temperature and stirred overnight, then quenched with 100ml of brine and extracted with ether (3×100 ml). The ether extracts werecombined, washed with 100 ml of water, 100 ml of brine, dried andevaporated to yield a residue which was chromatographed on silica (50:50ethyl acetate/hexane) to yield 2.1 g of compound 124 as a yellow oil.

Example 134 6-(1-naphthyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3-(1-naphthoyl)propionic acid

A mixture of naphthalene (40 g) and succinic anhydride (20 g) was addedto a well stirred suspension of aluminum trichloride (55 g) innitrobenzene (140 ml). The resulting mixture was stirred overnight atroom temperature. The mixture was then poured slowly onto ice-water (600g) and acidified with 6N-hydrochloric acid. The crude acid was filtered,washed with water until washings were neutral and recrystallized fromethanol yielding the product (m.p. 170°-172° C.).

b. 6-(1-naphthyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The propionic acid from part a was reacted essentially as described inExample 6a-b to obtain the expected product.

Example 139 2-(2-butynyl)-7-phenyl-1,2-diazapin-3-one

a. 7-phenyl-1,2-diazapin-3-one

To a mixture of 10g (0.052 mole) of 4-benzoylbutyric acid in 300 ml oftoluene, hydrazine was added in one portion and the reaction was heatedto reflux until all water had ceased to azeotrope. The reaction mixturewas cooled and the toluene was stripped off in vacuo. The residue wasdissolved in 200 ml Et₂ O and washed with H₂ O (100 ml) and brine (100ml). The ether extract was dried over anhydrous MgSO₄, filtered andstripped to yield an orange semisolid which was triturated with ether toyield 3.8 g (39%) of the desired product as a yellow solid.

b. 2-(2-butynyl)-7-phenyl-1,2-diazapin-3-one

The product from part a was alkylated essentially as described inExample 6b to yield 1.1 g of the desired product as a yellow oil.

Example 143 7-chloro-2,4,4a,5-tetrahydro-2-(2-pentyn-1-yl)-indeno1,2-c!-pyridazin-3-one

a. 2-carbomethoxy-5-chloroindanone

To a mixture of sodium hydride (2.4 g, 60% in mineral oil, 0.06 mole)and 50 ml dry dimethoxyethane, 5-chloroindanone (50 g, 0.03 mole) in 50ml dimethoxyethane was added dropwise at room temperature. The mixturewas stirred at room temperature until hydrogen evolution ceased. Thendimethylcarbonate (27 g, 0.3 mole) was added dropwise at roomtemperature and the reaction was heated to 60° C. for one hour. Thereaction was cooled to room temperature, quenched with 100 ml H₂ O,acidified to pH 5 with concentrated HCl and extracted with ethyl ether(3×100 ml). The ether extract was washed with brine (100 ml), dried overanhydrous MgSO₄ and stripped to yield 3.0 g (45%) of the desired productas a tan solid.

b. 2-carbomethoxy-2-carbomethoxymethyl-5-chloroindanone

To a mixture of sodium hydride (0.44 g, 60% in mineral oil, 0.0111 mole)and 50 ml dry dimethylformanide (DMF), the indanone ester from part a(2.5 g, 0.0111 mole) in 50 ml DMF was added dropwise with cooling. Thereaction mixture was stirred at 10° C. until all H₂ evolution ceased.Then methyl bromoacetate (1.9 g, 0.0122 mole) dissolved in 25 ml of DMFwas added dropwise at 10° C. The reaction was stirred at 5°-10° C. forone hour and overnight at room temperature, then quenched with H₂ O (100ml) and extracted with ether (3×100 ml). The organic layers werecombined and washed with H₂ O (100 ml) and brine (100 ml), then driedover anhydrous MgSO₄ and stripped to yield 3.0 g of a tan solid.

c. 7-chloro-2,4,4a,5-tetrahydro-indeno 1,2-c!-pyridazin-3-one

A mixture of the diester (2.5 g, 0.0084 mole) from part c and 100 ml of6N HCl was refluxed for 2 hours, until no starting material was detectedby thin layer chromatography. The reaction mixture was cooled to roomtemperature and poured into 200 ml of ice/water. A precipitate wasformed which was collected by vacuum filtration and washed with 200 mlH₂ O. The precipitate was dried overnight in vacuo at 40° C. to yield1.8 g, (95%) white solid.

d. 7-chloro-2,4,4a,5-tetrahydro-2-(2-pentyn-1-yl)-indeno1,2-c!-pyridazin-3-one

The ketoacid was reacted as described in Example 6a-b to yield Compound143. Compound 155 was prepared following essentially the same procedureand starting with 5-chloro-3-methylindanone.

Examples 145 and 146 5-(4-chlorophenyl)-1-(2-pentyn-1-yl)-2-pyridinoneand 5-(4-chlorophenyl)-3-cyano-1-(2-pentyn-1-yl)-2-pyridinone

a. 2-(4-chlorophenyl)-3-dimethylaminopropenal

Phosphorus oxychloride (92 g) was added dropwise to stirred DMF (78 ml)between 10°-15° C. To the resulting slurry was added4-chlorophenylacetic acid (34.12 g). The resulting mixture was stirredat room temperature for one half hour and then heated to 70°-80° C.during 5.5 hours, during which time the mixture became effervescent. Thereaction mixture was cooled and poured slowly onto cracked ice. Theresulting suspension was brought to pH 10 with solid potassiumcarbonate. Ice was added intermittently during this addition to maintainthe temperature below 15° C. Toluene (150 ml) was added and theresulting mixture heated at 100° C. for one hour. The mixture was cooledand allowed to stand overnight. The two resulting layers were separatedand the aqueous layer extracted with toluene (2×100 ml). The combinedorganic layers were washed with water (5×200 ml) and dried overanhydrous sodium sulfate. The solvent was evaporated in vacuo and theresulting yellow solid was triturated with hexane to yield 26 g of2-(4-chlorophenyl)-3-dimethylaminopropenal as a tan solid mp. 120°-125°C.

b. 3-cyano-5-(4-chlorophenyl)-2-pyridinone

To solution of sodium methoxide (7.52 g) in methanol (130 ml) was addedcyanoacetamide (5.84 g) followed by2-(4-chlorophenyl)-3-dimethylaminopropenal and the resulting suspensionwas refluxed overnight. During this time a yellow solid was formed. Themixture was cooled to room temperature and glacial acetic add (50 ml)was added followed by water (100 ml). The resulting yellow orange solidwas filtered off, washed several times with water and dried to yield 8.1g of 3-cyano-5-(4-chlorophenyl)-2-pyridinone.

c. 5-(4-chlorophenyl)-2-pyridinone

A mixture of 3-cyano-5-(4-chlorophenyl)-2-pyridinone (4.6 g) and 85% H₃PO₄ (60 ml) was heated at reflux for 16 hours. The resulting mixture wascooled to room temperature, poured into ice/water and filtered yielding3.1 g of 5-(4-chlorophenyl)-2-pyridinone as a yellow solid.

d. 5-(4-chlorophenyl)-1-(2-pentyn-1-yl)-2-pyridinone

To a suspension of NaH (60% in mineral oil, 200 mg) in dry DMF (50 ml)at 0° C. was added the preceding pyridinone and the mixture was stirredat 0° C. for one half hour. To the resulting suspension was added1-bromo-2-pentyne dropwise. The resulting mixture was kept at 0° C.during one half hour and poured into saturated aqueous ammonium chloride(200 ml). The aqueous suspension was extracted with ether (3×100 ml) andthe combined ether layers washed with brine and dried, yielding thecrude product. After column chromatography (silica gel, hexane:ethylacetate 8:2) the product was obtained as a white amorphous solid.

e. 5-(4-chlorophenyl)-3-cyano-1-(2-pentyn-1-yl)-2-pyridinone

3-Cyano-5-(4-chlorophenyl)-2-pyridinone was similarly alkylated to yield5-(4-chlorophenyl)-3-cyano-1-(2-pentyn-1-yl)-2-pyridinone, Compound 146.

Example 149 5-chloro-1-(2-pentyn-1-yl)-2-quinolinone

a. N-(4-chlorophenyl)cinnamamide

To a mixture of 4-chloroaniline (16.2 g), toluene (120 ml), and pyridine(11 ml) at 0° C., cinnamoyl chloride (20.0 g) in 120 ml of toluene wasadded dropwise. After stirring 15 minutes at 0° C. the reaction mixturewas poured into a mixture of ethyl acetate: water (250 ml:250 ml). Theorganic layer was separated and extracted with 5% aqueous HCl (3×250ml), water (1×250 ml), 5% aqueous sodium bicarbonate (3×250 ml), driedover anhydrous sodium sulfate and evaporated yielding the amide as awhite solid.

b. 5-chloro-2-quinolinone

To a mixture of N-(4-chlorophenyl)cinnamamide (8.3 g), and chlorobenzene(60 ml) was added portionwise aluminum chloride (21.4 g) under nitrogenat room temperature and the reaction mixture was slowly warmed up to125° C. and kept at that temperature for 3 hours. The reaction mixturewas cooled down and poured over 400 g of ice. The product crystallizedout as a pink solid which was filtered and dried.

c. 5-chloro-1-(2-pentyn-1-yl)-2-quinolinone

To a suspension of NaH (60% in mineral oil, 700 mg) in dry DMF (100 ml)at 0° C. was added the preceding quinolinone (2.05 g) and the mixturewas stirred at 0° C. for one half hour. To the resulting suspension wasadded 1-bromo-2-pentyne (1.6 g) dropwise. The resulting mixture was keptat 0° C. for one half hour and poured into saturated aqueous ammoniumchloride (200 ml). The aqueous suspension was extracted with ether(3×100 ml), the combined ether layers washed with brine and dried,yielding the crude product. Trituration with hexane yielded the productas a yellow solid (1 g).

Example 150 5-(4-chlorophenyl-1-(2-pentyn-1-yl)-2-pyrimidinone

a. 5-(4-chlorophenyl)-2-pyrimidinone

A mixture of 2-(4-chlorophenyl)dimethylaminopropenal (Example 145a)(5.13 g), urea (2.4 g), concentrated HCl (10 ml), water (4 ml) andethanol (150 ml) was refluxed for 4 hours. After cooling to roomtemperature concentrated ammonium chloride was added until the pH was 7.The resulting yellow solid was filtered off and dried yielding 1.5 g of5-(4-chlorophenyl)-2-pyrimidinone.

b. 5-(4-chlorophenyl)-1-(2-pentyn-1-yl)-2-pyrimidinone

To a suspension of NaH (60% in mineral oil, 340 mg) in dry DMF (75 ml)at 0° C. was added the preceding pyridinone (1.0 g) and the mixture wasstirred at 0° C. for one half hour. To the resulting suspension wasadded 1-bromo-2-pentyne (750 mg) dropwise. The resulting mixture waskept at 0° C. for one half hour and poured into saturated aqueousammonium chloride (200 ml). The aqueous suspension was extracted withether (3×100 ml), the combined ether layers washed with brine and dried,yielding the crude product. Trituration with hexane yielded the productas a yellow solid.

Example 151 5,5'- bis(pent-2-yn-1-yl)!-7-chloro-2,5-dihydroindeno-1,2-c!-(2H)-pyridazin-3-one

a. 7-chloro-2,5-dihydroindeno- 1,2-c!-(2H)-pyridazin-3-one

To a mixture of 2,4,4a,5-tetrahydroindeno- 1,2-c!-pyridazin-3-one (4.5g, Example 143c) and 100 ml of glacial acetic acid was added withstirring at room temperature, bromine (3.3 g) portionwise and thereaction mixture was refluxed for 3 hours. The reaction mixture wascooled to room temperature and poured in 200 ml of water to yield awhite precipitate which was collected by vacuum filtration, washed withwater and dried at 40° C. to yield 3.3 g of a tan solid.

b. 5,5'- bis(pent-2-yn-1-yl)!-7-chloro-2,5-dihydroindeno-1,2-c!-(2H)-pyridazin-3-one

The product for part a was alkylated with 1-bromo-2-pentyne as describedin Example 6b to yield a mixture of product and starting material whichwas purified by column chromatography (silica; 60% ethyl acetate/40%hexane).

Example 152 6-(4-chlorophenyl)-3-(2-pentyn-1-thio)-pyridazine

a. 6-(4-chlorophenyl)-pyridazinthione

A mixture of 3.0 g of 6-(4-chlorophenyl)-pyridazinone, 50 ml of drypyridine and 3.2 g of phosphorus pentasulfide was refluxed for 1 hour,evaporated to dryness and extracted with 200 ml of ether. The etherextract was washed with water (3×100 ml), brine (100 ml), dried overmagnesium sulfate and evaporated to yield 3.0 g of6-(4-chlorophenyl)-pyridazinthione as a yellow solid.

b. 6-(4-chlorophenyl)-3-(2-pentyn-1-thio)-pyridazine

The 6-(4-chlorophenyl)-pyridazinthione from part a was alkylated with1-bromo-2-pentyne following essentially the procedure described inExample 6b to yield 1.1 g of compound 152 as a white solid.

Example 1536-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinthione

A mixture of 6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone(3.0 g, 0.011 mole) 50 ml dry pyridine, and 2.5 g (0.011 moles) ofphosphorus pentasulfide was refluxed for one hour, cooled and thepyridine was evaporated in vacuo. The residue was dissolved in 200 ml ofethyl ether and washed with H₂ O (3×100) and brine (100 ml). The etherextract was dried over anhydrous MgSO₄, stripped to yield 2.6 g (82%) ofthe product as a yellow solid.

Example 156 7-chloro-2,4,4a,5-tetrahydro-2-(2-pentyn-4-ene-1-yl)indeno1,2-c!-pyridazin-3-one

a. 3-vinyl-2-propyn-1-ol

To a mixture of potassium hydroxide (1.7 g, 87%, powdered), FeCl₃ (0.1g), dimethyl sulfoxide (100 ml) and ether (100 ml) at 15° C. was added asolution of xylene-free vinyl acetylene (17 g) in 25 ml of ether. Thereaction mixture was stirred at 10°-15° C. for 1 hour, thenparaformaldehyde (4.5 g) was added in one portion and the mixture wasstirred for an additional hour, then quenched with 100 ml of saturatedbrine and extracted with ether (2×100 ml). The ether extracts werewashed with brine (100 ml), dried over magnesium sulfate and evaporatedto yield 20 g of the alcohol as a colorless liquid.

b. 7-chloro-2,4,4a,5-tetrahydro-2-(2-pentyn-4-ene-1-yl)-indeno1,2-c!-pyridazin-3-one

The final product was obtained using the alcohol from part a andfollowing essentially the procedures described in Examples 11a and 6b.

Example 1576-(4-chlorophenyl)-3-chloro-2-(2'-pentyn-1-yl)-2,5-dihydropyridazine

To a solution of 6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinone(compound 109) (3.0 g, 0.011 mole) in 100 ml dry DMF was cooled to 5° C.and phosphoryl chloride (4.2 g, 0.0275 mole) was added dropwise. Thesolution immediately turned bright yellow. After stirring for 16 hoursthe reaction mixture was poured into 200 ml of cold water and stirred toyield a fluffy yellow solid which was filtered off and dried in vacuo at30° C. to yield 3.0 g (93%) of the product as a yellow solid.

Compound 160 was prepared by the same method starting with phosphorusoxybromide in place of phosphorus oxychloride.

Example 1586-(4-chlorophenyl)-3-methoxy-2-(2'-pentyn-1-yl)-2,5-dihydropyridazine

A mixture of compound 157 (1.0 g, 0.00342 mole), sodium metal (0.08 g,0.00342 gram atoms) and 25 ml of anhydrous methanol was stirred at roomtemperature until all of the sodium metal reacted. The reaction mixturewas stirred overnight at room temperature. The methanol was evaporatedin vacuo and the residue was taken up in ethyl ether (100 ml). The ethersolution was washed with brine (100 ml), dried over anhydrous MgSO₄ andstripped to yield 0.45 g of the product as a yellow solid (45% yield).

Compound 159 was prepared analogously using potassium triazole in placeof sodium methoxide.

Example 1612-(4-chlorophenyl)-4-(2-pentyn-1-yl)-4H,6H-1,3,4-oxadiazin-5-one

a. N'-chloroacetyl-4-chlorobenzoic hydrazide

To a solution of p-chlorobenzoic hydrazide (11.2 g) in dioxane (100 ml)was added chloroacetyl chloride (6 ml). The resulting mixture wasrefluxed for three hours, cooled to room temperature and filtered. Theresulting solid was washed with ethyl ether and dried to yieldN'-chloroacetyl-4-chlorobenzoic hydrazide as white solid.

b. 5,6-dihydro-2-(4-chlorophenyl)-4H-1,3,4-oxadiazin-5-one

A mixture of the previous compound (6 g), sodium hydroxide (1.5 g) inDMF (75 ml) was heated at 130° C. for 2 hours with stirring. The cooledreaction mixture was poured into water, and the resulting precipitatewas filtered and recrystallized from ethanol/water yielding5,6-dihydro-2-(4-chlorophenyl)-4H-1,3,4-oxadiazin-5-one (2.3 g).

c. 2-(4-chlorophenyl)-4-(2-pentyn-1-yl)-4H, 6H-1,3,4-oxadiazin-5-one

The previous compound (1.8 g) was added to a mixture of sodium hydride(1.3 g, 60% in mineral oil) and DMF (75 ml) with stirring at 0° C. undernitrogen. The resulting mixture was stirred at 0° C. for 30 minutes and1-bromo-2-pentyne (1.45 g) was added dropwise with stirring at 0° C. Thereaction mixture was stirred at 0° C. for 1 hour, poured into ice-water(150 g), and filtered to yield the product as a yellow solid.

Example 1622-(4-chlorophenyl)-3-(2-pentyn-1-yl)-3H,6H-1,3,4-oxadiazin-2-one

a. 4-chloro-α-hydroxy-acetophenone

Iodobenzene diacetate (67.33 g) was added during 15 minutes to a stirredsolution of p-chloroacetophenone (32.2 g) and potassium hydroxide (68.5g) in methanol (400 ml) which was kept at 0° C., and the mixture wasallowed to warm up to room temperature, stirred for 3 hours and thenevaporated to dryness under reduced pressure. The residue was shakenwith water (300 ml) and ethyl ether (300 ml) and the ether solution wasseparated, dried over magnesium sulfate and evaporated to dryness. Amixture of the residue, ethanol (70 ml) and aqueous 2N hydrochloric acid(70 ml) was stirred at room temperature overnight and then filtered, andthe solid product was recrystallized from methanol to yield4-chloro-α-hydroxy-acetophenone (17.5 g).

b. 4-chloroacetophenone ethoxycarbonylhydrazone

A mixture of the above compound (16.4 g), ethyl carbazate (10.5 g) andethanol (400 ml) was stirred at room temperature for five days and thenconcentrated to small volume by evaporation. The residue was heateduntil a clear solution was obtained, and then cooled and filteredyielding 4-chloroacetophenone ethoxycarbonylhydrazone as a white solid(16.0 g).

c. 5-(4-chlorophenyl)-3H,6H-1,3,4-oxadiazin-2-one

Sodium hydride (0.5 g, 60% in mineral oil) was added to a stirredsolution of the above compound (11.4 g) in ethanol (250 ml) and themixture was stirred at room temperature overnight and then filtered. Thesolid product formed was filtered and dried to yield5-(4-chlorophenyl)-3H,6H-1,3,4-oxadiazin-2-one as a white solid (8.2 g).

d. sodium salt of 5-(4-chlorophenyl)-3H,6H-1,3,4-oxadiazin-2-one

Sodium hydride (2.0 g, 60% in mineral oil) was added to a stirredsolution of the above compound (8.2 g) in tetrahydrofuran (300 ml). Theresulting mixture was stirred at room temperature until the gasevolution stopped, the solvent was evaporated under vacuum and theresidue was triturated with hexane yielding the sodium salt of5-(4-chlorophenyl)-3H,6H-1,3,4-oxadiazin-2-one as a white solid (10.4g).

e. 2-(4-chlorophenyl)-3-(2-pentyn-1-yl)-3H,6H-1,3,4-oxadiazin-2-one

The previous compound (2.0 g) was dissolved in DMF (75 ml) with stirringat 0° C. under nitrogen. To the resulting mixture was added1-bromo-2-pentyne (1.5 g) dropwise with stirring at 0° C. The reactionmixture was stirred at 0° C. during 1 hour, poured into ice-water (150g), and filtered to yield the product as a yellow solid (2.5 g).

Compounds 163 and 164 were prepared using essentially the sameprocedure.

Example 1655-(4-chlorophenyl)-3-(2-pentyn-1-yl)-3H,6H-1,3,4-thiadiazin-2-one

a. 5-(4-chlorophenyl)-3H,6H-1,3,4-thiadiazin-2-one

A mixture of 2-bromo-p-chloroacetophenone (9.16 g),methoxythiocarbonylhydrazine (13.0 g) and acetonitrile (75 ml) wasrefluxed overnight and then cooled and filtered. The light yellow solidwas washed with hexane and dried yielding5-(4-chlorophenyl)-3H,6H-1,3,4-thiadiazin-2-one (4.3 g).

b. salt of 5-(4-chlorophenyl)-3H, 6H-1,3,4-thiadiazin-2-one

Sodium hydride (0.5 g, 60% in mineral oil) was added to a stirredsolution of the above compound (2.0 g) in THF (100 ml). The resultingmixture was stirred at room temperature until the gas evolution stopped,the solvent was evaporated under vacuum and the residue was trituratedwith hexane yielding the sodium salt of5-(4-chlorophenyl)-3H,6H-1,3,4-thiadiazin-2-one.

c. 5-(4-chlorophenyl)-3-(2-pentyn-1-yl)-3H, 6H-1,3,4-thiadiazin-2-one

The previous compound was dissolved in DMF (75 ml) with stirring at 0°C. under nitrogen. To the resulting mixture was added 1-bromo-2-pentyne(1.5 g) dropwise with stirring at 0° C. The reaction mixture was stirredat 0° C. during 2 hours, poured into ice-water (150 g) and filtered toyield the product as a yellow solid.

Example 200 4,4a,5,6-tetrahydro-8-chloroh!-cinnolin-2-(2'-pentynyl)-3-one

a. 4-(3-chlorophenyl)-butyric acid

To a 300 ml round-bottomed flask equipped with magnetic stirrer andreflux condenser was charged 23.7 g of 87% potassium hydroxide and 150ml of diethyleneglycol, With stirring, 23 g of3-(3-chlorobenzoyl)propionic acid was added followed by 24 g of 85%hydrazine. The mixture was heated to reflux for 2 hours when 50 ml ofsolvent was azeotroped off into a Dean-Stark trap. The reaction wasrefluxed for an additional 2 hours, cooled, and poured into 500 g of icewith 50 ml of con. hydrochloric acid. A white precipitate was formedwhich was extracted into 400 ml of ethyl ether, and washed with 100 mlof water and 100 ml of saturated sodium chloride solution. The etherextract was dried over anhydrous magnesium sulfate, filtered, andstripped to yield 19.5 g of product as a white solid.

b. 4-(3-chlorophenyl)-butyryl chloride

To a dry 100 ml flask equipped with a magnetic stirrer and refluxcondenser was charged the product from part a and 20 ml of thionylchloride. The solution was refluxed for 2 hours, cooled, and stripped toyield 18 g of product as a yellow oil.

c. 6-chlorotetralone

To a dry 500 ml flask equipped with side-arm addition funnel,thermometer, nitrogen inlet, and magnetic stirrer, was charged 33 g ofanhydrous aluminum chloride and 200 ml of dry carbon disulfide. Theproduct from part b (18 g) was added dropwise to the mixture and thereaction was refluxed for 2.5 hours. The reaction was then cooled andpoured into 300 g of ice-water and extracted with 3×100 ml of ethylether. The ether extract was washed with 100 ml of water and 100 ml ofsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and stripped to yield 7.5 g of product as a yellowliquid.

d. 6-chloro-2-(carboxymethylidene)-tetralone

To a dry 250 ml flask equipped with side-arm addition funnel,thermometer, and magnetic stirrer was charged 6.7 g of sodiummetaperiodate in 40 ml of water. The solution was cooled to 5° C. andtreated with 0.6 ml of con. sulfuric acid followed by a solution of 4.7g of D-tartaric acid in 9 ml of water, and 20 ml of absolute ethanol.The mixture was stirred for 16 hours at room temperature, warmed to 80°C. for 10 minutes, cooled, and diluted with 150 ml of water. The basicsolution was washed once with 100 ml of ethyl ether, and addified to pH4 with 1N hydrochloric acid. The resulting precipitate was collected byvacuum filtration and dried overnight in vacuo at 30° C. to yield 7.2 gof product as a white solid.

e. 6-chloro-2-(carboxylmethylene)-tetralone

To a dry 100 ml flask equipped with magnetic stirrer was charged 7.2 gof the product from part d, 20 ml of water, 50 ml of glacial aceticacid, and 3.8 g of zinc dust. The reaction was warmed to 50° C. for 1hour and stirred overnight at ambient temperature. The reaction was thenpoured into 100 ml of ethyl acetate, filtered, and washed with 100 ml ofwater and 100 ml of saturated sodium chloride solution. The ethylacetate extract was dried over anhydrous magnesium sulfate; filtered,and stripped to yield 6.0 g of product as a white solid.

f. 4,4a,5,6-tetrahydro-8-chlorobenzo h!cinnolin-3-(2H)-one

The product from part e was treated with hydrazine using essentially thesame procedure described for 12 d to yield 5.7 g of product as a tansolid.

g. 4,4a,5,6-tetrahydro-8-chlorobenzo h!cinnolin-2-(2'-pentynyl)-3-one

The product was prepared from the product in part f using essentiallythe same procedure described for example 12 e.

Example 201 6-(4-chlorophenyl)-2-methyl-4,5-dihydropyridazinone

To a 250 ml flask equipped with magnetic stirrer and reflux condenserwas charged 10 g of 3-(4-chlorobenzoyl)-propionic acid, 250 ml ofabsolute ethanol, and 2.5 ml of methyl hydrazine. The reaction wasrefluxed for 3 hours and cooled to yield a solid which was collected byvacuum filtration, washed with 50 ml of hexane, and air dried. Isolated9.5 g of product as a white solid.

Example 202 5,6-dihydro-8-chlorobenzo h!cinnolin-3-(2'-pentynyl)-one

The product from 200, part f, was oxidized and alkylated usingessentially the same procedures described for example 109 a,b.

Example 2036-(4-chlorophenyl)-4-(2'-pentynyl)-2-methyl-4,5-dihydropyridazinone

To a dry 250 ml flask equipped with nitrogen inlet, side-arm additionfunnel, thermometer, and magnetic stirrer, was charged 3.0 g of compound201 and 75 ml of anhydrous ethyl ether. The solution was cooled to -78°C. with a dry ice acetone bath and 8.4 ml of 1.6M n-butyl lithium wasadded dropwise. The reaction was stirred at -78° C. for 0.5 hours and1.98 g of pentynyl bromide was then added dropwise in 25 ml of ether.The reaction was stirred at -70° C. for 1 hour and overnight at ambienttemperature. The reaction was then quenched with 100 ml of water andextracted with 3×100 ml of ethyl ether. The ether extract was washedwith 100 ml of water and 100 ml of saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered, and stripped to yellowoil which was chromatographed on silica gel with 30% ethyl acetate,hexane. Isolated 0.7 g of product as a white solid.

Example 2046-(4-chlorophenyl)-2-(5-methyl-2-furanylmethylene)pyridazinone

a. 2-chloromethyl-5-methylfuran

To a dry 200 ml flask equipped with reflux condenser, magnetic stirrer,nitrogen inlet, and side-arm addition funnel was charged 10 g of2-dimethylaminomethyl-5-methylfuran and 50 ml of hexane. At roomtemperature, 7.8 g of ethyl chloroformate was added dropwise, and thesolution was then refluxed for 2 hours. Vacuum distillation (0.5 mm Hg,60°-65° C.), afforded 1 g of pure product.

b. 6-(4-chlorophenyl)-2-(5-methyl-2-furanylmethylene)pyridazinone

The product was prepared from the product in part a using essentiallythe same procedure described for example 12 e.

Example 205 6-(4-chlorostyryl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3-(4-chlorocinnamoyl)-propionic acid

To a dry 250 ml flask equipped with a magnetic stirrer, Dean-Stark trap,and reflux condenser was charged 15 g of 4-chlorobenzaldehyde, 12.4 glevulenic acid, 5.7 ml of piperidine, and 100 ml of toluene. Thereaction was refluxed for 3 hours, after which no water was observed toazeotrope from the solution. The reaction was cooled and stripped toyield a reddish-brown liquid which was triturated with hexane to yield11.2 g of product as a yellow solid.

b. 6-(4-chlorostyryl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product from part a was cyclized with hydrazine and alkylated withpentynyl mesylate using essentially the same procedures described forexample 12 d-e.

Example 2066-(4-chlorophenethyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 6-(4-chlorophenethyl)-2(H)-4,5-dihydropyridazinone

4.5 g of 6-(4-chlorostyryl)-2(H)-4,5-dihydropyridazinone was dissolvedin 200 ml of methoxyethanol and charged to a 500 ml Parr® hydrogenationbottle. 1 g of 10% palladium on carbon was added as a slurry inmethoxyethanol and the reaction was treated with hydrogen on a Parr®apparatus at 50 psi and ambient temperature. When the theoretical amountof hydrogen was consumed (35 min.) the hydrogenation was stopped and thecatalyst was filtered off. The organic solvent was stripped off and theresidue was chromatographed on silica gel with 50% ethyl acetate, hexaneto yield 3.2 g of the product as a yellow solid.

b. 6-(4-chlorophenethyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product from part a was alkylated with pentynyl mesylate usingessentially the same procedure described for example 12d.

Example 2076-(3,4-methylenedioxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from piperonylic acid using essentially thesame procedures described for example 12b-e.

Example 2086-(4-chlorophenyl)-2-(1-methyl-2-pentynyl)-4,5-dihydropyridazinone

a. 3-hexyn-2-yl-methyl sulfonate

The mesylate of 3-hexyn-2-ol was prepared using essentially the sameprocedure described for example 11a.

b. 6-(4-chlorophenyl)-2-(1-methyl-2-pentynyl)-4,5-dihydropyridazinone

6-(4-chlorophenyl)-4,5-dihydropyridazinone was alkylated with theproduct from part a using essentially the same procedure described forexample 6b.

Example 209 6-(2-fluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-fluorobenzoyl chloride using essentiallythe same procedures described for example 12b-e

Example 210 6-(2-methylphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-methylbenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 211 6-(2-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-chlorobenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 212 6-(2-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-methoxybenzoyl chloride usingessentially the same procedures described for example 12b-e.

Example 2136-(3-trifluoromethylphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-trifluoromethylbenzoyl chloride usingessentially the same procedures described for example 12b-e.

Example 214 6-(3-fluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-fluorobenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 215 6-(3-methylphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-methylbenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 216 6-(3-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-chlorobenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 217 6-(3-cyanophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-cyanobenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 218 6-(3-nitrophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-nitrobenzoyl chloride using essentiallythe same procedures described for example 12b-e.

Example 219 6-(3-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-methoxybenzoyl chloride usingessentially the same procedures described for example 12b-e.

Example 2206-(3-methoxy-4-methylphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-methoxy-4-methyl benzoic acid usingessentially the same procedures described for example 12b-e.

Example 2216-(3-chloro-4-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-chloro-4-methoxy benzoic acid usingessentially the same procedures described for example 12b-e.

Example 2226-(3-bromo-4-fluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-bromo-4-fluorobenzoic acid usingessentially the same procedures described for example 12b-e.

Example 2236-(3-nitro-4-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-nitro-4-methoxy benzoic acid usingessentially the same procedures described for example 12b-e.

Example 2246-(3,4-difluorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3,4 difluoro benzoic acid usingessentially the same procedures described for example 12b-e.

Example 2256-(3-fluoro-4-methylphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 3-fluoro-4-methyl benzoic acid usingessentially the same procedures described for example 12b-e.

Example 2266-(3-nitro-4-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3-nitro-4-methoxy benzoic acid

To a 500 ml erlenmeyer flask with magnetic stirrer was charged 10.3 g of3-nitro-4-methoxy-methylbenzoate, 400 ml tetrahydrofuran, and 3.2 g of86% potassium hydroxide. The reaction was stirred for 12 hours atambient temperature, after which the resulting solid was collected byvacuum filtration and washed with 2×100 ml of ethyl ether. The solid wasdissolved in 200 ml of water and acidified to pH 4 with 6N hydrochloricacid. The resulting precipitate was collected by vacuum filtration,washed with 200 ml water, and dried overnight in vacuo at 30° C.Isolated 7.4 g of product as a white solid.

b. 6-(3-nitro-4-methoxyphenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product from part a was converted to the product using essentiallythe same procedures described for example 12b-e.

Example 2276-(9,10-dihydro-2-phenanthrene)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 9,10-dihydro-omega-oxo-2-phenanthrenebutyric acid using essentially the same procedures described for example6a-b.

Example 228 5,6-diphenyl-4-cyano-2-(2'-pentynyl)-pyridazinone

The product was prepared from2,3-dihydro-3-oxo-5,6-diphenyl-4-pyridazine carbonitrile usingessentially the same procedure described for example 12e.

Example 229 6-(2-quinoline)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-quinoline carboxylic acid usingessentially the same procedure described for example 12b-e.

Example 230 6-(2-quinoxaline)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product was prepared from 2-quinoxaloyl chloride using essentiallythe same procedure described for example 12b-e.

Example 2316-(4-chlorophenyl)-2-(3,5-dimethyl-4-isoxolylmethyl)-4,5-dihydropyridazinone

The product was prepared from 4-(chloromethyl)-3,5-dimethylisoxozoleusing essentially the same procedure described for example 6b.

Example 232 8-(2'-pentynyl)-acenaphtho 1,2c!pyridazin-9-one

a. methyl(Z)-(1,2-dihydro-2-oxo-1-acenaphthyleneylidene)acetate

To a 500 ml flask equipped with magnetic stirrer, thermometer, nitrogeninlet, and side-arm addition funnel was charged 8.4 gmethyl-(triphenylphosphoranylidene)-acetate and 200 ml of absoluteethanol. A precipitate formed immediately. The reaction was stirred atambient temperature for 2 hours, and the precipitate was then collectedby vacuum filtration. Isolated 4.4 g of product as a yellow solid.

b. 8-(H)-acenaphtho 1,2c!pyridazin-9-one

To a 200 ml flask equipped with magnetic stirrer and reflux condenserwas charged 2.5 g of the product from part a and 100 ml of chloroform.At room temperature, 0.45 ml of 85% hydrazine was added and the reactionwas refluxed for a total of 2 hours. Upon cooling, a precipitate wasformed which was collected by vacuum filtration. Isolated 0.5 g of theproduct as a yellow solid.

c. 8-(2'-pentynyl)-acenaphtho 1,2c!pyridazin-9-one

The product from part b was alkylated with pentynyl mesylate usingessentially the same conditions described for example 12e.

Example 233 6-(4-chlorophenyl)-2-(acetylhydrazide)-4,5-dihydropyridazinone

a. 6-(4-chlorophenyl)-2-(ethylacetyl)-4,5-dihydropyridazinone

To a dry 100 ml flask equipped with magnetic stirrer and refluxcondenser was charged 10 g of (4-chlorobenzoyl)-propionic acid, 50 mlabsolute ethanol, and 5.3 g triethyl amine. With stirring, 7.3 g ofethyl hydrazinoacetate hydrochloride was added portionwise and thereaction was refluxed for 3 hours. Upon cooling, a white crystallinesolid formed which was collected by vacuum filtration, and washed with100 ml hexane. Isolated 13.3 g of product as a white solid.

b. 6-(4-chlorophenyl)-2-(acetyl hydrazide)-4,5-dihydropyridazinone

To a 100 ml flask equipped with magnetic stirrer and reflux condenserwas charged the product from part a (10.2 g), 10 ml water, and 6.1 ml of85% hydrazine. The reaction was heated to 70° C. for 6 hours, cooled,and diluted with 200 ml of cold water. The resulting solid was collectedby vacuum filtration and dried overnight in vacuo at 40° C. to yield 9.6g of product as a white solid.

Example 234 6-(4-chlorophenyl)-2-N-acetylhydrazide-(N'-2,4-pentanedione-hydrazone)!-4,5-dihydropyridazinone

To a dry 100 ml flask equipped with magnetic stirrer and refluxcondenser was charged 1 g of compound 233, 30 ml of absolute ethanol,and 0.4 ml of 2,4-pentanedione. After refluxing for 1 hour, the solventwas stripped off and the residue was triturated with hexane to yield 0.7g of product as a pale yellow solid.

Example 235 6-(3-thianaphthene)-2-(2'-pentynyl)-4,5-dihydropyridazinone

a. 3-thianaphtheneoyl acrylic acid

To a 250 ml flask equipped with Dean-Stark trap, reflux condenser, andmagnetic stirrer, was charged 5 g of 3-acetyl thianaphthene, 100 ml oftoluene, and 3.9 g of glyoxylic acid hydrate. The reaction was refluxedand azeotroped for 2.5 hours after which the toluene was removed byvacuum distillation. The resulting residue was washed with hexane toyield a solid which was collected by vacuum filtration to yield 6 g ofproduct as a yellow solid.

b. 6-(3-thianaphthene)-2 H!-4,5-dihydropyridazinone

The product from part a was charged to a 100 ml flask equipped withmagnetic stirrer and reflux condenser. 60 ml of glacial acetic acid and20 ml of water was added followed by 2.5 g of zinc dust. The reactionwas heated to 50° C. for 2 hours, cooled, and poured into 150 ml ofethyl acetate. The insoluble material was filtered off and the ethylacetate extract was washed with 100 ml of water, 100 ml of saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered and stripped. The residue was redissolved in 50 ml of absoluteethanol and treated with 0.75 ml of 85% hydrazine. After refluxing for 3hours, the reaction was cooled to yield a solid which was collected byvacuum filtration. Isolated 3.7 g of product as a yellow solid.

c. 6-(3-thianaphthene)-2-(2'-pentynyl)-4,5-dihydropyridazinone

The product from part b was alkylated with pentynyl mesylate withessentially the same procedure described for example 12e.

Example 236 6-(3-thianaphthene)-2-(2'-pentynyl)-pyridazinone

The product was isolated from the silica gel column chromatography (30%ethyl acetate,hexane) of the crude product from compound 235.

Example 2376-(4-chlorophenyl)-2-(3,5-dimethyl-1-pyrazoylmethylene)-4,5-dihydropyridazinone

The product was prepared from compound 233 using essentially the sameprocedure used to prepare compound 234 with 0.5 ml of 6N hydrochloricacid as a catalyst. Isolated 0.9 g of product as a white solid.

Example 2386-(4-chlorophenyl)-2-(1,3,4-oxadiazin-2-one-5-yl-methylene)-4,5-dihydropyridazinone

To a 100 ml flask equipped with magnetic stirrer, side-arm additionfunnel, thermometer, and nitrogen inlet was charged 1.5 g of compound233 and 30 ml of methylene chloride. At room temperature, a solution of0.54 g triphosgene in 30 ml of methylene chloride was added dropwise.The reaction was refluxed for 1 hour, cooled, and stripped to yield awhite solid which was slurried in hexane and collected by vacuumfiltration. Isolated 1.55 g of product as a white solid.

Example 239 6-(4-chlorophenyl)-2-1,3,4-oxadiazin-2-one-3-(2'-pentynyl)-5-yl-methylene!-4,5-dihydropyridazinone

To a dry 100 ml flask equipped with magnetic stirrer, side-arm additionfunnel, thermometer, and reflux condenser was charged 0.5 g compound238, 0.45 g potassium carbonate, and 50 ml of dry acetone. The reactionwas stirred for 1 hour at room temperature and 0.3 g of pentynylmesylate was added dropwise in 5 ml of acetone. The reaction wasrefluxed for 1 hour, cooled, and filtered. The filtrate was stripped toyield a yellow solid which was dissolved in 100 ml of ethyl acetate andwashed with 100 ml of water and 100 ml of saturated sodium chloridesolution. The ethyl acetate extract was the dried over anhydrousmagnesium sulfate, filtered, and stripped to yield 0.6 g of product as awhite solid.

Example 240 6-(4-chlorophenyl)-2-N-acetylhydrazide-(N'-3,5-dichloro-2-hydroxy-phenylhydrazone)!-4,5-dihydropyridazinone

To a dry 100 ml erlenmeyer flask was charged 0.65 g compound 233, 25 mlethanol, and 0.45 g of 3,5-dichloro salicylaldehyde. To the stirringsolution was the added 5 drops of glacial acetic add. The reaction wasstirred for 2 hours at room temperature, after which the resultingprecipitate was collected by filtration and washed with 50 ml of hexane.Isolated 0.9 g of product as a yellow solid.

Example 241 6-(4-chlorophenyl)-2-1,3,4-oxadiazin-2-one-3-(3'-iodopropargyl)-5-yl-methylene!-4,5-dihydropyridazinone

a. 6-(4-chlorophenyl)-2-1,3,4-oxadiazin-2-one-3-(propargyl)-5-yl-methylene-4,5-dihydropyridazinone

Compound 238 was alkylated with propargyl bromide using essentially thesame procedure used to prepare compound 239.

b. 6-(4-chlorophenyl)-2-1,3,4-oxadiazin-2-one-3-(3'-iodopropargyl)-5-yl-methylene!-4,5-dihydropyridazinone

To a dry 100 ml flask equipped with magnetic stirrer and refluxcondenser was charged 0.5 g of the product from part a, 0.4 g ofN-iodosuccinimide, 10 mg of silver nitrate, and 40 ml of dry acetone.The reaction was stirred for 16 hours at ambient temperature, pouredinto 100 ml of acetone, and filtered to remove solids. The acetonefiltrate was stripped and the residue was redissolved in 150 ml of ethylacetate. The ethyl acetate extract was washed with 100 ml of water, 100ml of saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and stripped to yield 0.5 g of the product as ayellow viscous liquid.

The compounds of the present invention have fungitoxic activity,particularly against phytopathogenic fungi. They are active againstfungi of a number of classes including Deuteromycetes (FungiImperfecti), Basidiomycetes and Ascomycetes. More particularly, themethod of this invention provides for activity against organismsincluding Pyricularia oryzae, Pyrenophora trichostoma, Fusarium species,Erysiphe graminis, Puccinia recondita, alsa leucostoma, Colletotrichumlagenarium, Nectria galligena, Cochliobolus miyabeanus, Thanatephoruscucumeris, Pseudocercosperella herpotrichioides, Helminthosporiumspecies, Monilinia fructicola, Sclerotium rolfsii, Venturia inequalis,Botryotinia fuckeliana, Diaporthe citri, Rhizopus stolonifer,Verticillium albo-atrum, Phytophthora capsici, Alternaria solani,Ustilago maydis, Pythium ultimum, Leptosphaeria nodorum, Schlerotiniaspecies, Sphaerotheca fuliginea, Gymnosporangium asiaticum, Alternariaalternata, Uncinula necator, and Podosphaera leucotricha. Moreparticularly, rice diseases are controlled by the method of theinvention. Examples of such rice diseases are seedborne diseases such asthose incited by Cochliobolus miyabeanus and Pyricularia oryzae,soilborne diseases such as Fusarium species, Rhizoctonia species, andRhizopus species, and seedling box and field diseases such as thoseincited by Pyricularia oryzae, Thanatephorus cucumeris and Cochliobolusmiyabeanus. Additional diseases include powdery mildew incited bySphaerotheca fulignea (e.g., cucurbit powdery mildew), Uncinula necator(e.g., grape powdery mildew), and Podosphaera leucotricha (e.g., applepowdery mildew).

The compounds of the invention also control wood decay fungi such asGleophyllum trabeum, Phialophora mutabilis, Poria palcenta and Trametesversicolor. Accordingly, the present invention also encompasses the useof the compounds as wood preservatives.

The compounds of the invention can be applied as fungicidal sprays bymethods commonly employed, such as conventional high-gallonage hydraulicsprays, low-gallonage sprays, air-blast, aerial sprays and dusts. Suchuse conveniently permits treatment of fungal infestations in crops suchas vegatables, fruits, ornamentals, seeds, turf, cereal and vines amongother plants. The dilution and rate of application will depend upon thetype of equipment employed, the method and frequency of applicationdesired and diseases to be controlled, but the effective amount isusually from about 0.01 kilogram (kg) to about 20 kg, of activeingredient (a.i.) per hectare. As a foliar fungicide, the pyridazinoneis usually applied to growing plants at a rate of about 0.1 to about 5and preferably from about 0.125 to about 0.5 kg per hectare.

As a seed protectant, the amount of toxicant coated on the seed isusually at a dosage rate of about 10 to about 250 grams (g) andpreferably from about 20 to about 60 g per 50 kilograms of seed. As asoil fungicide, the chemical can be incorporated in the soil or appliedto the surface usually at a rate of 0.5 to about 20 kg and preferablyabout 1 to about 5 kg per hectare.

The compounds of the present invention are useful for the control offungi and can be utilized at various loci such as the seed, the watersurface, the soil or the foliage. For such purposes, these compounds canbe used in the technical or pure form as prepared, as solutions or asformulations. The compounds are usually taken up in a carrier or areformulated so as to render them suitable for subsequent use asfungicides. For example, these chemical agents can be formulated aswettable powders, dry powders, emulsifiable concentrates, dusts,granular formulations, aerosols, or flowable emulsion concentrates. Insuch formulations, the compounds are extended with a liquid or solidcarrier and when desired suitable surfactants are incorporated.

It is usually desirable, particularly in the case of foliar sprayformulations, to include adjuvants, such as wetting agents, spreadingagents, dispersing agents, stickers, adhesive and the like in accordancewith agricultural practices. Such adjuvants commonly used in the art canbe found in McCutcheon's Emulsifiers and Detergents, McCutcheon'sEmulsifiers and Detergents/Functional Materials and McCutcheon'sFunctional Materials all published annually by McCutcheon Division of MCPublishing Company (New Jersey).

In general, the compounds utilized in this invention can be dissolved inappropriate solvents such as acetone, methanol, ethanol,dimethylformamide or dimethyl sulfoxide and such solutions extended withwater. The concentrations of the solution can vary from 1% to 90% with apreferred range being 5 to 50%.

For the preparation of emulsifiable concentrates, the compounds of theinvention can be dissolved in suitable organic solvents or a mixture ofsolvents, together with an emulsifying agent which permits dispersion ofthe fungicide in water. The concentration of the active ingredient inemulsifiable concentrates is usually 10% to 90% and in flowable emulsionconcentrates; this can be as high as 75%.

Wettable powders suitable for spraying can be prepared by admixing thecompound with finely divided solid, such as days, inorganic silicatesand carbonates, and silicas and incorporating wetting agents, stickingagents, and/or dispersing agents in such mixtures. The concentration ofactive ingredients in such formulations is usually in the range of 20%to 98%, preferably 40% to 75%. A typical wettable powder is made byblending 50 parts of6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone, 45 parts ofa synthetic precipitated hydrated silicon dioxide sold under thetrademark Hi-Sil® and 5 parts of sodium lignosulfonate (Marasperse®N-22). In another preparation of a Kaolin type, (Barden) day is used inplace of the Hi-Sil in the above-wettable powder and in another suchpreparation 25% of the Hi-Sil is replaced with a synthetic sodiumsilicoaluminate sold under the trademark Zeolex® 7.

Dusts are prepared by mixing the compounds of the invention with finelydivided inert solids which can be organic or inorganic in nature.Materials useful for this purpose include botanical flours, silicas,silicates, carbonates and days. One convenient method for preparing adust is to dilute a wettable powder with a finely divided carrier. Dustconcentrates containing 20% to 80% of the active ingredient are commonlymade and are subsequently diluted to 1% to 10% use concentration.

The compounds of the present invention may be utilized in combinationwith other fungicides such as:

(a) dithiocarbamate and derivatives such as: ferbam, ziram, maneb,mancozeb, zineb, propineb, metham, thiram, the complex of zineb andpolyethylene thiuram disulfide, dazomet, and mixtures of these withcopper salts;

(b) nitrophenol derivatives such as: dinocap, binapacryl, and2-sec-butyl-4,6-dinitrophenyl isopropyl carbonate;

(c) heterocyclic structures such as: captan, folpet, glyodine,anilazine, ditalimfos, 4-butyl-1,2,4-triazole, 5-amino-1-bis(dimethylamino)phosphinyl!-3-phenyl-1,2,4-triazole, etradiazole,dithianon, thioquinox, benomyl, thiabendazole,4-(2-chlorophenylhydrazono)-3-methyl-5-isoxazolone, vinclozolin,iprodione, procymidone, triadimenol, triadimefon, bitertanol,prochloraz, fenarimol, bis-(p-chlorophenyl)-3-pyridinemethanol,bis-(p-chlorophenyl)-5-pyrimidinemethanol, triarimol, flutriafol,flusilazole, propiconazole, ectaconazole, myclobutanil, fenbuconazole{i.e., alpha-2-(4-chlorophenyl)ethyl!-alpha-phenyl-1H-1,2,4-triazole-1-propanenitrile},hexaconazole, cyproconazole, terbuconazole, diniconazole, fluoroimide,pyridine-2-thiol-1-oxide, 8-hydroxyquinoline sulfate and metal saltsthereof, 2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiin-4,4-dioxide,2,3-dihydro-5-carboxanilido-6-methyl-1,4-oxathiin, cis-N-(1,1,2,2-tetrachloroethyl)thiol!-4-cyclohexene-1,2-dicarboximide,cycloheximide, dehydroacetic acid, captafol, ethirimol, quinomethionate,D,L-methyl-N-(2,6-dimethylphenyl)-N-(2'-methoxyacetyl)alanine methylester, D,L-methyl-N-(2,6-dimethylphenyl)-N-chloroacetyl-D,L-2aminobutyrolactone, D,L-N-(2,6-dimethylphenyl)-N-(phenylacetyl)alaninemethyl ester,5-methyl-5-vinyl-3-(3,5-dichlorophenyl)-2,4-dioxo-1,3-oxazolidine,3-(3,5-dichlorophenyl)-5-methyl-5-(methoxymethyl)-1,3-oxazolidi-2,4-dione,3-(3,5-dichlorophenyl)-1-isopropylcarbamoylhydantoin, 2-cyano-N-(ethylaminocarbonyl)-2-methoximino!cetamide, fenpropimorph,fenpropidine, 2,6-dimethyl-N-tridecylmorpholine, dodemorph, andtriforine;

(d) miscellaneous halogenated fungicides such as: chlorothalonil,dichlone, chloroneb, tricamba, TCPN, dichloran, 2-chloro-1-nitropropane,polychloronitrobenzenes such as pentachloronitrobenzene (PCNB), andtetrafluorodichloroacetone;

(e) fungicidal antibiotics such as: griseofulvin, kasugamycin, polyoxin,validamycin, and streptomycin;

(f) copper-based fungicides such as: copper hydroxide, cuprous oxide,basic cupric chloride, basic copper carbonate, copper terephthalate,copper naphthenate and Bordeaux mixture; and

(g) miscellaneous fungicides such as: dodine, phenylmercuric acetate,N-ethylmercuri-1,2,3,6-tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexachlorophthalimide,phenylmercuric monoethanol ammonium lactate, p-dimethylaminobenzenesodium sulfonate, methyl isothiocyanate, 1-thiocyano-2,4-dinitrobenzene,1-phenylthiosemicarbazide, nickel-containing compounds, calciumcyanamide, lime sulfur, thiophanate-methyl, flutolanil, edifenphos,isoprothiolane, probenazole, iprobenfos, tricyclazole, and pyroquilon.

It is particularly advantageous to utilize the present invention incombination with a dithiocarbamate, e.g., mancozeb or maneb, for addedcontrol of non-phycomycetes fungi.

The compounds of examples 1-165 and 200-241 were tested for theirfungicidal activity. The compounds were tested in vivo and/or in vitroagainst the following organisms: Pyricularia oryzae, Pyrenophoratrichostoma, Fusarium species , Erysiphe graminis, Puccinia recondita,Valsa leucostoma, Colletotrichum lagenarium, Nectria galligena,Cochliobolus miyabeanus, Thanatephorus cucumeris, Pseudocercosperellaherpotrichioides, Helminthosporium species, Monilinia fructicola,Sclerotium rolfsii, Venturia inequalis, Botryotinia fuckeliana,Diaporthe citri, Rhizopus stolonifer, Verticillium albo-atrum,Phytophthora capsici, Alternaria solani, Ustilago maydis, Pythiumultimum, Leptosphaeria nodorum, Schlerotinia species, Sphaerothecafuliginea, Gymnosporangium asiaticum, Alternaria alternata, Uncinulanecator, and Podosphaera leucotricha, according to the followingmethods:

I. In Vitro Tests--Fungitoxicity Assay

Compounds were assayed for activity by the broth-dilution (BD) method orthe agar-dilution (AD) method. In the agar-dilution method, potatodextrose agar was amended with a solution of the test compounds,solubilized in dimethyl sulfoxide or similar solvent at theconcentration indicated in Table VI, then inoculated with a 6 mm plug offungal mycelium. The radial growth was measured for each sample, andcorrected for inoculum size. The percent growth inhibition is equal tothe radial growth of the control sample (A) minus the radial growth oftreated sample (B) divided by the radial growth of the control sample(A) times 100 as seen by the following equation. ##EQU1##

In the broth-dilution method, test compounds dissolved in dimethylsulfoxide were added at the concentration indicated in Table VI to YDbroth (2% dextrose, 0.4% yeast extract) and incubated with fungalinoculum for 48 hours at 28° C. in an environmental shaker, at 200 rpm.Growth inhibition was determined by dry weight measurement according tothe following formula: ##EQU2##

The results of the in vitro tests are reported in Table VI.

                  TABLE VI                                                        ______________________________________                                        IN VITRO BIOLOGICAL DATA                                                      Cmpd         % growth      Cmpd        % growth                               No.   ppm    inhibition                                                                             test*                                                                              No.   ppm   inhibition                                                                           test*                           ______________________________________                                         1.   5      92.7     BD    33.  100   27.6   BD                               2.   100    0        BD    34.  10    100.0  BD                               3.   100    53.6     BD    35.  50    85.0   BD                               4.   100    26.7     BD    36.  50    100.0  BD                               5.   100    75.0     BD    37.  100   100.0  BD                               6.   100    91.5     BD    38.  100   75.2   BD                               7.   100    94.4     BD    39.  50    94.6   BD                               8.   100    96.2     BD    40.  5     95.7   BD                               9.   100    94.4     BD    41.  10    89.2   BD                               10.  100    100.0    BD    42.  10    91.7   BD                               11.  10     87.7     BD    43.  10    22.3   BD                               12.  1      96.0     BD    44.  5     87.0   BD                               13.  10     87.0     BD    45.  10    100.0  BD                               14.  50     100.0    BD    46.  100   100.0  BD                               15.  50     37.1     BD    47.  50    100.0  BD                               16.  50     12.7     BD    48.  50    100.0  BD                               17.  25     91.9     BD    49.  50    100.0  BD                               18.  5      88.4     BD    50.  50    100.0  BD                               19.  100    96.8     BD    51.  50    100.0  BD                               20.  10     100.0    BD    52.  50    93.7   BD                               21.  100    45.8     BD    53.  50    100.0  BD                               22.  100    99.7     BD    54.  200   71.4   AD                               23.  5      100.0    BD    55.  50    100.0  BD                               24.  200    6.1      AD    56.  1     100.0  BD                               25.  50     100.0    BD    57.  100   95.7   BD                               26.  50     96.3     BD    58.  10    39.8   BD                               27.  50     100.0    BD    59.  10    100.0  BD                               28.  1      100.0    BD    60.  10    100.0  BD                               29.  1      86.1     BD    61.  10    95.3   BD                               30.  50     41.2     BD    62.  1     100.0  BD                               31.  5      92.4     BD    63.  200   100.0  AD                               32.  100    100.0    BD    64.  25    100.0  AD                               65.  50     84.0     AD   103.  1     100.0  AD                               66.  25     100.0    AD   104.  5     100.0  AD                               67.  5      83.6     BD   105.  10    33.3   AD                               68.  5      10.4     BD   106.  50    81.0   AD                               69.  50     100.0    BD   107.  200   83.7   AD                               70.  5      100.0    BD   108.  5     100.0  BD                               71.  50     92.6     BD   109.  1     100.0  AD                               72.  0.5    96.2     BD   110.  10    100.0  BD                               73.  50     94.4     BD   111.  25    100.0  BD                               74.  1      100.0    AD   112.  10    100.0  BD                               75.  100    100.0    AD   113.  10    64.3   BD                               76.  10     100.0    AD   114.  5     100.0  BD                               77.  10     89.2     BD   115.  50    93.7   BD                               78.  0.5    100.0    BD   116.  50    82.5   BD                               79.  50     17.0     AD   117.  200   34.7   BD                               80.  2.5    100.0    AD   118.  200   100.0  AD                               81.  2.5    95.8     AD   119.  5     99.3   BD                               82.  2.5    100.0    AD   120.  1     100.0  AD                               83.  0.5    81.3     AD   121.  1     100.0  AD                               84.  50     75.8     BD   122.  100   84.6   AD                               85.  100    100.0    AD   123.  100   100.0  AD                               86.  100    80.0     AD   124.  10    100.0  BD                               87.  100    100.0    AD   125.  0.5   89.5   AD                               88.  100    80.0     AD   126.  10.   100.0  AD                               89.  10     100.0    AD   127.  1     100.0  AD                               90.  1      100.0    AD   128.  0.156 100.0  AD                               91.  1      100.0    AD   129.  1     100.0  AD                               92.  1      100.0    BD   130.  1     100.0  AD                               93.  0.5    100.0    AD   131.  1     100.0  AD                               94.  10     22.2     AD   132.  200   91.8   AD                               95.  10     22.2     AD   133.  200   67.4   AD                               96.  10     94.5     AD   134.  50    66.5   BD                               97.  1      100.0    AD   135.  94.4  94.4   BD                               98.  10     40.0     AD   136.  1     84.6   BD                               99.  1      100.0    AD   137.  200   18.4   AD                              100.  0.16   100.0    AD   138.  100   64.6   BD                              101.  1      100.0    AD   139.  100   65.0   BD                              102.  1      100.0    AD   140.  100   37.8   BD                              141.  100    23.9     BD   154.  10    16.0   AD                              142.  50     100.0    BD   155.  10    92.0   AD                              143.  1      100.0    AD   156.  1     100.0  AD                              144.  1      100.0    BD   157.  10    100.0  AD                              145.  1      96.0     BD   158.  10    100.0  AD                              146.  10     5.0      BD   159.  1     100.0  AD                              147.  50     98.1     BD   160.  1     100.0  AD                              148.  10     0        BD   161.  1     75.9   AD                              149.  50     51.5     BD   162.  10    96.9   AD                              150.  50     48.2     BD   163.  10    12.7   AD                              151.  100    80.6     BD   164.  100   14.2   AD                              152.  10     18.2     AD   165.  100   100.0  AD                              153.  10     90.9     AD                                                      200.  10     100      AD   224.  50    100    AD                              201.  10     10       AD   225.  50    100    AD                              202.  10     100      AD   226.  50    100    AD                              203.  10     100      AD   227.  10    30     AD                              204.  10     100      AD   228.  10    50     AD                              205.  10     100      AD   229.  5     100    AD                              206.  1      14.3     AD   230.  10    30     AD                              207.  1      100      AD   231.  10    36     AD                              208.  1      28.6     AD   232.  5     45.5   AD                              209.  50     85.7     AD   233.  100   21     AD                              210.  50     35       AD   234.  100   42     AD                              211.  50     30       AD   235.  100   100    AD                              212.  50     35       AD   236.  100   100    AD                              213.  50     100      AD   237.  100   58     AD                              214.  50     100      AD   238.  100   31.6   AD                              215.  50     100      AD   239.  100   100    AD                              216.  50     100      AD   240.  100   14     AD                              217.  50     100      AD   241.  100   100    AD                              218.  50     100      AD                                                      219.  50     100      AD                                                      220.  50     100      AD                                                      ______________________________________                                         *AD = agar dilution, BD = broth dilution                                 

II In Vivo Tests

Compounds were tested at 200 ppm as a twenty-four hour preapplicationprotectant test prior to inoculation.

a) Rice Blast (RB) Pyricularia Oryzae

Two week old M201 rice plants were inoculated with 250,000 spores perpot of Magnaporthe grisea (Pyricularia oryzae) by spraying the leavesand stems with an atomizer. The inoculated plants were incubated in amist cabinet at 80° F. for 48 hours, then placed in a greenhouseenvironment (70°-80° F.). Six days after inoculation the plants wereevaluated for percent disease control compared to check plants with theaid of standard area disease diagrams.

b) Rice Sheath Blight (RSB)

Thanatephorus cucumeris (Rhizoctonia solani) mycelia were grown for sixdays in potato dextrose broth in shake culture. Drained mycelial matswere blended with an approximately equal weight of rice flour and fiveparts water. This slurry was dispensed onto the soil surface of potscontaining rice seedlings previously treated with experimentalcompounds. The plants were placed in a mist chamber at 25°-28° C. for 48hours. Following two more days at 25° C. and 70-90% relative humiditythe plants were evaluated for percent disease control compared to checkplants.

The results of the in vivo tests are reported in Table VII.

                  TABLE VII                                                       ______________________________________                                        IN VIVO BIOLOGICAL RESULTS                                                    at 200 ppm                                                                    Cmpd  % Control Cmpd    % Control                                                                             Cmpd  % Control                               No.   RB     RSB    No.   RB   RSB  No.   RB   RSB                            ______________________________________                                        1.    90     0      34.   90   --   71.   0    --                             2.    0      0      35.   75   --   72.   90   --                             3.    0      0      36.   90   --   73.   95   --                             4.    0      0      37.   90   --   74.   75   --                             5.    0      50     38.   75   --   75.   0    --                             6.    0      0      39.   0    --   76.   0    --                             7.    0      0      40.   0    --   77.   0    --                             8.    0      0      41.   0    --   78.   0    --                             9.    0      0      43.   0    --   79.   100  75                             10.   --.sup.a                                                                             80     45.   0    --   80.   99   0                              11    0      0      46.   0    --   81.   95   --                             12.   99     50     47.   0    --   82.   0    --                             13.   50     50     48.   90   --   83.   90   --                             14.   0      --     49.   90   --   84.   95   0                              15.   0      50     50.   0    --   85.   0    --                             16.   0      50     51.   100  --   86.   0    --                             17.   0      80     52.   0    --   87.   75   --                             18.   0      0      53.   100  --   88.   0    --                             19.   50     0      54.   0    --   89.   95   0                              20.   0      0      55.   0    --   90.   0    95                             21.   0      0      56.   100  --   91.   90   --                             22.   75     --     57.   0    --   92.   90   --                             23.   50     --     58.   0    --   93.   0    --                             24.   0      --     59.   0    --   94.   0    --                             25.   50     --     60.   50   --   95.   0    --                             26.   95     --     61.   90   --   96.   0    --                             27.   0      --     62.   99   --   99.   0    --                             28.   95     --     63.   0    --   100.  100  0                              29.   95     --     64.   0    --   101.  75   0                              31.   90     --     65.   0    --   102.  99   0                              32.   0      --     66.   0    --   103.  95   0                              33.   0      --     70.   0    --   104.  0    0                              105.  75     0      123.  99   --   145.  95   0.sup.a                        106.  0      --     124.  0    --   146.  0    --                             107.  0      0      125.  0    --   148.  0    --                             108.  95     50     127.  0    --   149.  100  --                             109.  99     100    128.  95   0    150.  99   95                             110.  0      --     129.  0    0    151.  0    --                             111.  0      --     132.  0    0    152.  0    --                             112.  90     --     133.  0    --   153.  0    --                             113.  95     --     134.  0    --   154.  50   0                              114.  50     --     135.  0    --   155.  100  90                             115.  50     --     136.  99   --   156.  100  95                             116.  0      --     137.  0    --   157.  10   0                              117.  0      --     138.  0    --   158.  0    --                             118.  0      --     139.  0    --   159.  0    0                              119.  95.sup.a                                                                             0.sup.a                                                                              140.  75   --   160.  0    95                             120.  99     --     141.  0    --   161.  99   0                              121.  95     --     142.  50   --                                             122.  0      --     143.  99   --                                             ______________________________________                                         "--" means not tested                                                         .sup.a Tested at 100 ppm                                                 

The compounds of the invention are also active against Candida albicans.Accordingly, the compounds of this invention can be used to controlCandida albicans and dermatophytes, such as Trichophyton species, forexample in humans by application in a known pharmaceutically acceptablecarrier by means known to one skilled in the art.

The activity against Candida albicans was determined using the followingtest protocol.

1. Inoculum preparation

Conidia and mycelium from the Candida albicans culture maintained onpotato dextrose agar plates were lightly scraped off into yeastextract-dextrose broth (YDB) so that mostly conidia was used asinoculum. The conidial suspsension was strained through a double layerof cheesecloth to remove mycelial dumps. The inoculum mixture was placedin microtiter plates using a 12-tipped pipet. 175 microliters wereplaced in each well of the microtiter plates and the plates were placedin the refrigerator overnight. There were two replications.

2. Addition of the compounds

The compounds to be tested were dissolved in 1:1 acetone:methanol and100 ppm of the compound solution were placed in a well of the preparedmicrotiter plates.

3. Incubation and rating

The microtiter plates were incubated for 7 days at room temperatureafter addition of the compounds. Percent control was visually estimatedusing a microtiter plate reading mirror. Readings were made at 1, 2, 3,and/or 7 days after treatment.

The results are listed in Table VIII.

                  TABLE VIII                                                      ______________________________________                                        % CONTROL OF GROWTH                                                           Cmpd    ppm       +1     +2      +3   +7                                      ______________________________________                                         12     100       100    100     100  100                                     109     100       100    100     100  100                                     119     100       100    100     100  100                                      56     100       100    100     100                                          120     100       100    100     100                                           76     100       100    100     100                                           34     100       100    100     100                                          161     100       100    100     100                                          121     100       100    100     100                                          127     100       100    100     100                                          153     100       100    100     100                                          156     100       100    100     100                                          100     100       100    100     100                                          128     100       100    100     100                                          130     100       100    100     100                                          131     100       100    100     100                                          229     100       100    100     100                                          ______________________________________                                    

It has been found unexpectedly that compositions comprising certaincompounds of the present invention in admixture with certain knownfungicidal compounds have an enhanced fungicidal activity which isgreater than the expected additive sum of the activities of theindividual components of the composition. The expected activity, E, fora given combination of active fungicidal components can be calculated inaccordance with the Colby formula:

    E=X+Y-(X*Y/100),

wherein

X=disease control action (in percent) of a first fungicidel,

Y=disease control action (in percent) of a second fungicide, and

E=expected action of the first and second fungicide in admixture. SeeColby, L. R., "Calculating synergistic and antagonistic responses ofherbicide combinations", Weeds, 15. pp. 20-22 (1967) and Limpel et al.,"Weeds control by . . . certain combinations", Proc. NEWCL, 16, pp.48-53 (1962).!

The ratio of the fungicidal components of the composition having thisenhanced property can vary over a range of ratios dependent upon theparticular components and conditions of use. In general, such acomposition will comprise at least a sufficient amount of each componentin an effective ratio to produce compositional fungicidal activitygreater than the expected additive sum of the activities of theindividual components of the composition. Preferably, the observed,actual fungicidal activity is at least about one-half percent (0.5%)greater than, more preferably at least about five percent (5%) greaterthan the expected additive sum of the activities of the individualcomponents of the composition. When properly measured, there is anobserved E value greater than, preferably significantly greater than,the expected Colby formula-calculated E value, i.e.--(Actual E/ExpectedE) greater than 1; preferably (Actual E/Expected E) greater than 1.005;and more preferably (Actual E/Expected E) greater than 1.05.

The present invention also embodies a composition having enhancedfungicidal properties and comprising

(i) one or more compounds having the formula6-(3-A-4-B-phenyl)-2-(C)-pyridazinone, wherein A represents a hydrogenor fluoro substituent; B represents a hydrogen, chloro, or bromosubstituent; and C represents a 2'-pentynyl, a 3'-vinyl-2'-propynyl, a4'-fluoro-2'-pentynyl or a 5'-fluoro-2'-pentynyl substituent; or6-(3-A'-4-B'-phenyl)-2(C')-4,5-dihydropyridazinone, wherein A'represents a hydrogen or fluoro substituent; B' represents a hydrogen,bromo, or chloro substituent; and C' represents a 2'-pentynyl, a3'-vinyl-2'-propynyl, a 4'-fluoro-2'-pentynyl or a 5'-fluoro-2'-pentynylsubstituent; and

(ii) one or more fungicidal compounds selected from mancozeb, maneb,iprodione, chlorothalonil, probenazole, pyroquilon and fenbuconazole.

A preferred composition having enhanced fungicidal properties includesone or more compositions having the formula6-(3-A-4-B-phenyl)-2-(C)-pyridazinone is6-(3-A-4-chlorophenyl)-2-(C)-pyridazinone wherein A is either a fluoroor hydrogen substituent and C is either a 2'-pentynyl or a3'-vinyl-2'-propynyl substituent. More preferred is6-(4-chlorophenyl)-2-(2'-pentynyl)-pyridazinone,6-(3-fluoro-4-chlorophenyl)-2-(2'-pentynyl)-pyridazinone,6-(4-chlorophenyl)-2-(3'-vinyl-2'-propynyl)-pyridazinone, or6-(3-fluoro-4-chlorophenyl)-2-(3'-vinyl-2'-propynyl)pyridazinone.

A preferred compound having enhanced fungicidal properties includes oneor more compositions having the formula6-(3-A'-4-B'-phenyl)-2-(C')-4,5-dihydropyridazinone is6-(3-A'-4-chlorophenyl)-2-(C')-4,5-dihydropyridazinone wherein A' iseither a fluoro or hydrogen substituent and C' is either a 2'-pentynylor a 3'-vinyl-2'-propynyl substituent. More preferred is6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone,6-(3-fluoro-4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone,6-(4-chlorophenyl)-2-(3'-vinyl-2'-propynyl)-4,5-dihydropyridazinone, or6-(3-fluoro-4-chlorophenyl)-2-(3'-vinyl-2'-propynyl)-4,5-dihydropyridazinone.

Preferred combinations having enhanced properties include (i)6-(4-chlorophenyl)-2-(2'-pentynyl)-pyridazinone, (ii)6-(3-fluoro-4-chlorophenyl)-2-(2'-pentynyl)-pyridazinone, or (iii)6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone, incombination with mancozeb, probenazole, pyroquilon, iprodione,fenbuconazole, or chlorothalonil.

More preferred combinations are6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinone in combination withmancozeb, probenazole, pyroquilon, iprodione, or fenbuconazole; and6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone incombination with chlorothalonil.

Preferably, in such combinations having enhanced properties, the ratioof either pyradizinone or the dihydro pyradizinone compound to the otherfungicide compound can range from about 25/1 to about 1/25. Illustrativepreferred approximate ratios are as follows:

(i) When Component I is 6-(4-chlorophenyl)-2-(2'-pentynyl)pyridazinonein combination with

    ______________________________________                                                       preferred ratio                                                                          more preferred ratio                                Component II   of I/II (by ppm)                                                                         of I/II                                             ______________________________________                                        (1)    mancozeb    20/1 to 1/20                                                                             4/1 to 1/4                                      (2)    probenazole 20/1 to 1/20                                                                             16/1 to 1/16                                    (3)    pyroquilon  25/1 to 1/25                                                                             16/1 to 1/16                                    (4)    iprodione   10/1 to 1/10                                                                             4/1 to 1/4                                      (5)    fenbuconazole                                                                             10/1 to 1/10                                                                             4/1 to 1/4                                      ______________________________________                                    

(ii) When component I is6-(4-chlorophenyl)-2-(2'-pentynyl)-4,5-dihydropyridazinone incombination with chlorothalonil, a preferred ratio is 20/1 to 1/20, morepreferably a ratio of 4/1 to 1/4.

The methods of use of the compositions of the present invention havingenhanced activity include those methods described above for thefungicides when used alone. Benefits can be obtained from the use ofthese compositions having enhanced activity since lesser amounts of thefungicides can be utilized for particular applications as compared tothe use of the individual compound alone or greater spectrum and lengthof activity at the same or lesser concentrations than those combinationsof fungicides which do not have enhanced activities.

The following experiments are illustrative of the compositions havingenhanced activity and activities of the present invention describedabove, but are not intended to be limitations on the scope of thesecombinations:

EXPERIMENTAL PROCEDURES

The experiments below were performed using the relevant followingprocedures.

Experimental compounds and commercial fungicides were tank mixed andmechanically sprayed at varying concentrations in a 1:1:2 mixture ofacetone, methanol and water. Protective or preventive sprays wereapplied one day before spore inoculation. Curative or post-infectionsprays were applied one day after spore inoculation. The spraying systemutilized delivered a 200 ppm dose at the rate of 1458 liters perhectare. The following details were applicable for the specifieddiseases:

Rice Blast Pyricularia Experiments

M-201 rice plants were inoculated with Pyricularia oryzae conidia. Thespore concentration was 300,000 to 500,000 conidia per milliliter inwater. An atomizer was used to apply twenty milliliters of inoculum totwenty plants per flat. The plants were placed in a humidity cabinet at100% relative humidity for 48 hours and then placed in a greenhouse.Evaluations were made 7-8 days after inoculation.

Wheat Septoria Experiments

Fielder wheat plants were inoculated with Septoria nodorum conidia. Thespore concentration was approximately 3,000,000 conidia per milliliterin water. An atomizer was used to apply twenty milliliters of inoculumto twenty plants per flat. The plants were placed in a humidity cabinetat 100% relative humidity for 72 hours and then placed in a greenhouse.Evaluations were made 10 days after inoculation.

Tomato Botrytis Experiments

Three week-old "Pixie" tomato plants were inoculated with Boytrytiscinerea conidia. The plants were held in dim light for two days prior toinoculation. The spore concentration was 500,000 to 650,000 conidia permilliliter of dextrose solution. An atomizer was used to apply theconidial suspension in a heavy coating to near runoff to both the upperand lower leaf surfaces and to the plant stem. The plants were kept in acontinuous mist chamber with a day-night cycle and at 20 degreescentigrade for 5 days.

"Disease control" was recorded as percent control based on a comparisonof the unsprayed, inoculated controls and the treated, inoculatedplants. The rates of application are indicated in the Tables.

                  TABLE IX                                                        ______________________________________                                        Rice Blast Protectant Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-               pyridazinone (component "A") and mancozeb (component "B")                     Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       99                                              50      --           --        0                                              12      --           --        0                                              --      200          --       99                                              --      50           --       75                                              200     50           99       99                                              50      50           75       99                                              12      50           75       99                                              ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        Rice Blast Curative Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-                 pyridazinone (component "A") and mancozeb (component "B")                     Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       80                                              50      --           --       50                                              12      --           --        0                                              --      200          --        0                                              --       50          --        0                                              --      200          80       90                                              50      200          50       80                                              12      200           0       50                                              ______________________________________                                    

                  TABLE XI                                                        ______________________________________                                        Rice Blast Protectant Using 6-(4-chloropheny1)-2-(2'-pentynyl)-4,5-           dihydropyridazinone (component "A") and chlorothalonil                        (component "B")                                                               Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       50                                              50      --           --       50                                              12      --           --        0                                              --      200          --       99                                              --      50           --        0                                              --      12           --        0                                              200     50           50       90                                              50      50           50       75                                              12      50            0       75                                              ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Rice Blast Protective Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-               pyridazinone (component "A") and probenazole (component "B")                  Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       80                                              50      --           --        0                                              12      --           --        0                                              --      200          --        0                                              --       50          --        0                                              --       12          --        0                                              200     200          80       90                                              50      200           0       80                                              12      200           0       50                                              ______________________________________                                    

                  TABLE XIII                                                      ______________________________________                                        Rice Blast Protective Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-               pyridazinone (component "A") and pyroquilon (component "B")                   Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       80                                              50      --           --        0                                              12      --           --        0                                              --      200          --       85                                              --      50           --        0                                              --      12           --        0                                              200     200          97       90                                              50      200          85       90                                              12      200          85       90                                              200     50           80       90                                              50      50            0       90                                              12      50            0        0                                              200     12           80       85                                              50      12            0       50                                              12      12            0       50                                              ______________________________________                                    

                  TABLE XIV                                                       ______________________________________                                        Wheat Septoria Preventative Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-         pyridaxinone (component "A") and iprodione (component "B")                    Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       50                                              50      --           --       50                                              12      --           --        0                                              --      200          --       50                                              --      50           --        0                                              --      12           --        0                                              200     50           50       90                                              50      50           50       80                                              12      50            0       80                                              ______________________________________                                    

                  TABLE XV                                                        ______________________________________                                        Tomato Botrytis Protective Using 6-(4-chlorophenyl)-2-(2'-pentynyl)-          pyridazinone (component "A") and fenbuconazole (component "B")                Rate ppm             % Disease Control                                        A       B            Calculated                                                                             Observed                                        ______________________________________                                         0       0           --        0                                              200     --           --       75                                              50      --           --        0                                              --      50           --       75                                              --      25           --       75                                              --       6           --       50                                              200     50           93       90                                              50      50           75       90                                              12      50           75       90                                              ______________________________________                                    

What is claimed is:
 1. A method for controlling phytopathogenic funguswhich comprises applying a fungicidally effective amount of a compoundof the formula ##STR90## wherein the compound is a six member ring and Ais --CR² ═N--Z--;D is nitrogen; Q is an aromatic group selected from##STR91## X is oxygen (O) or sulfur (S); Z is carbonyl (C═O), orthiocarbonyl (C═S); wherein(i) R¹ is alkyl, hydroxyalkyl, cyanoalkyl,cycloalkylalkyl, heterocyclylalkyl, phenyl, phenylalkyl, phenylcarbonyl,alkenyl, haloalkenyl, phenylalkenyl, alkynylalkenyl, alkynyl,haloalkynyl, phenylalkynyl, heterocyclyl, dialkynyl,heterocyclylalkynyl, cycloalkylalkynyl, alkenylalkynyl, hydzoxyalkynyl.alkoxyalkynyl, alkanoyloxyalkynyl, formylalkynyl, trialkylsilylalkynyl,trialkyltinalkynyl, haloalkenylalkynyl, carboxyalkynyl, oralkoxycarbonylalkynyl; R² is hydrogen or halogen; R³ and R⁶ areindependently hydrogen, alkoxy or halogen; R⁴ is hydrogen, halogen,alkoxy or nitro; R⁵ is hydrogen, halogen, nitro, alkyl, alkoxy,alkylthio, haloalkyl, haloalkoxy, haloalkylthio, phenyl, phenoxy orcyano; or(ii) R² and R³ together form a (C₁ --C₃)alkyl, (C₂ -C₃)alkyleneor carbonyl link and R¹, R⁴, R⁵, and R⁶ are as above;and agronomicallyacceptable salts thereof.
 2. A method for controlling a fungal infectionof a mammal which comprises applying to the fungus or its habitat afungicidally effective amount of a compound of the formula ##STR92##wherein the compound is a six member ring and A is --CR² ═N--Z--;D isnitrogen; Q is an aromatic group selected from ##STR93## X is oxygen (O)or sulfur (S): Z is carbonyl (C═O), or thiocarbonyl (C═S); wherein(i) R¹is alkyl, hydroxyalkyl, cyanoalkyl, cycloalkylalkyl, heterocyclylalkyl,phenyl, phenylalkyl, phenylcarbonyl, alkenyl, haloalkenyl,phenylalkenyl, alkynylalkenyl, alkynyl, haloalkynyl, phenylalkynyl,heterocyclyl, dialkynyl, heterocyclylalkynyl, cycloalkylalkynyl,alkenylalkynyl hydroxyalkynyl, alkoxyalkynyl, alkanoyloxyalkynyl,formylalkynyl, trialkylsilylalkynyl, trialkyltinalkynyl,haloalkenylalkynyl, carboxyalkynyl, or alkoxycarbonylalkynyl; R² ishydrogen or halogen; R³ and R⁶ are independently hydrogen, alkoxy orhalogen; R⁴ is hydrogen, halogen, alkoxy or nitro; R⁵ is hydrogen,halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy,haloalkylthio, phenyl, phenoxy or cyano; or(ii) R² and R³ together forma (C₁ -C₃)alkyl, (C₂ -C₃)alkylene or carbonyl link and R¹, R⁴, R⁵, andR⁶ are as above;and agronomically acceptable salts thereof.
 3. A methodfor preserving wood which comprises contacting the wood with afungicidally effective amount of a compound of the formula ##STR94##wherein the compound is a six member ring and A is --CR² ═N--Z--;D isnitrogen; Q is an aromatic group selected from ##STR95## X is oxygen (O)or sulfur (S); Z is carbonyl (C═O), or thiocarbonyl (C═S); wherein(i) R¹is alkyl, hydroxyalkyl, cyanoalkyl, cycloalkylalkyl, heterocyclylalkyl,phenyl, phenylalkyl, phenylcarbonyl, alkenyl, haloalkenyl,phenylalkenyl, alkynylalkenyl, alkynyl, haloalkynyl, phenylalkynyl,heterocyclyl, dialkynyl, heterocyclylalkynyl, cycloalkylalkynyl,alkenylalkynyl, hydroxyalkynyl, alkoxyalkynyl, alkanoyloxyalkynyl,formylalkynyl, trialkylsilylalkynyl, trialkyltinalkynyl,haloalkenylalkynyl, carboxyalkynyl, or alkoxycarbonylalkynyl; R² ishydrogen or halogen; R³ and R⁶ are independently hydrogen, alkoxy orhalogen; R⁴ is hydrogen, halogen, alkoxy or nitro; R⁵ is hydrogen,halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy,haloalkylthio, phenyl, phenoxy or cyano; or(ii) R² and R³ together forma (C₁ -C₃)alkyl, (C₂ -C₃)alkylene or carbonyl link and R¹, R⁴, R⁵, andR⁶ are as above;and agronomically acceptable salts thereof.